Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.CC1(C)[O:33][C@H:32]([CH:34]=O)[CH2:31][O:30]1.Cl.CO>>[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH2:34][C@@H:32]([OH:33])[CH2:31][OH:30])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)OC[C@@H](C=O)O1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Br
Agent: Cl
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NC[C@@H](O)CO)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The preparation is carried out starting from 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrobromide and (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde. The protecting group is cleaved off by means of a 1.25 N HCl/methanol solution: The reaction mixture was stirred at room temperature for 5 h, evaporated to dryness and dried under a high vacuum. The product was converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=C(C2C=CC=CC=2)C(C2C=CC=CC=2)=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([C:50]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=O)=O)=[CH:44][CH:43]=1>>[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[C:50]([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)=[N:22][C:21]3[C:26](=[CH:27][CH:28]=[C:19]([C:8]4[N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[C:11]5[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=5[N:9]=4)[CH:20]=3)[N:25]=2)=[CH:44][CH:43]=1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)c(-c4ccccc4)nc3c1)n2C1CCCCC1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(F)cc4)c(-c4ccc(F)cc4)nc3c1)n2C1CCCCC1

Procedure:
Prepared as described for Compound 406 using 4,4′-difluorobenzil in place of benzil.
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]3[NH:26][CH2:25][CH2:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=3[CH:31]=2)=[CH:13][CH:12]=1)[CH3:9]>C1COCC1>[CH2:8]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:26]([CH:1]=[O:3])[CH2:25][CH2:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=3[CH:31]=2)=[CH:15][CH:16]=1)[CH3:9]
Reactant: CC(=O)O
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.18 ml) was added dropwise formic acid (0.09 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at 50° C. for 2 hours. To the mixture was added THF (2 ml) and then was added dropwise, under ice-cooling a solution of methyl 7-(4-ethoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25 g) in THF (15 ml), and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-(4-ethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.24 g) as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccccc4F)ncnc32)CC1

Procedure:
4-[4-(2-Fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure A by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2-fluorophenol (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in acetonitrile. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.97-2.07 (m, 4H), 2.97-3.07 (m, 2H), 4.05-4.12 (m, 2H), 4.98-5.05 (m, 1H), 7.31-7.50 (m, 4H), 8.38 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=414.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[CH3:22].S(=[N:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])=O.NC1C=C(C=CC=1)C(O)=O.N1C=CC=CC=1>ClCCl.S(Cl)(Cl)=O>[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)([OH:14])[C:10]([F:11])([F:12])[F:13])=[CH:4][C:3]=1[CH3:22])=[O:30]
Reactant: Cc1cc(C(O)(c2ccc(F)cc2)C(F)(F)F)cc(C)c1N
Reactant: O=S=Nc1cccc(C(=O)Cl)c1
Agent: Nc1cccc(C(=O)O)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(O)(c2ccc(F)cc2)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Reaction time: 1 h

Procedure:
To a solution of 1-(4-amino-3,5-dimethyl-phenyl)-2,2,2-trifluoro-1-(4-fluorophenyl)-ethanol (Example I3) (0.313 g, 1.0 mmol) in absolute dichloromethane (10 ml), at 20° C., was added sequentially a solution of 3-sulfinylamino-benzoyl chloride (0.201 g, 1.0 mmol) (the 3-sulfinylamino-benzoyl chloride was prepared in situ by refluxing 3-amino-benzoic acid in thionyl chloride) in absolute dichloromethane (1 ml) and a solution of pyridine (0.087 g, 1.1 mmol) in absolute dichloromethane (1 ml). After one hour, the reaction mixture was quenched by addition of water (0.5 ml) and aqueous hydrochloric acid (1M) (1 ml). After separation of the phases, the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography over silica gel (eluent: ethyl acetate/hexanes 1:3 to 1:1). The title compound was isolated as colorless crystals.
Reaction SMILES: [F:1][C@@H:2]1[CH2:19][C@@:18]2([CH3:20])[CH:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:21])[CH2:4][C:3]1=O.[ClH:23].Cl.[NH:25]1[CH2:29][CH2:28][C@@H:27]([O:30][NH2:31])[CH2:26]1>N1C=CC=CC=1>[ClH:23].[NH:25]1[CH2:29][CH2:28][C@@H:27]([O:30]/[N:31]=[C:3]2\[CH2:4][CH:5]3[C@:18]([CH3:20])([CH2:19][C@H:2]\2[F:1])[C@@H:17]2[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6]3)[CH2:26]1
Reactant: NO[C@@H]1CCNC1
Reactant: C[C@]12C[C@@H](F)C(=O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12C[C@@H](F)/C(=N/O[C@@H]3CCNC3)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
2α-Fluoroandrostane-3,17-dione (315 mg) and 3-(R)-pyrrolidinyloxyamine dihydrochloride (Preparation 12, 190 mg) were dissolved in pyridine (5 ml) and stirred at RT for 1 h. After evaporation of the solvent, the crude reaction mixture was purified by flash chromatography (SiO2, CHCl3/MeOH/26% NH4OH 90/10/1). To the resulting oil obtained after fractions evaporation, dissolved in a 1/1 mixture of EtOAc/Et2O (20 ml) and cooled with an ice bath, an excess of 2N HCl solution in Et2O was added. The title compound I-bh was obtained, after filtration, as a white solid in 91% yield.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].[O:9]=[C:10]1[C:16]2[CH:17]=[CH:18][C:19]([C:21](OCCN(C)C)=[O:22])=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:29]=[CH:30][CH:31]=[CH:32][C:11]1=2>>[O:9]=[C:10]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([O:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:22])=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:29]=[CH:30][CH:31]=[CH:32][C:11]1=2
Reactant: CCN(CC)CCO
Reactant: CN(C)CCOC(=O)c1ccc2c(=O)c3ccccc3ccc2c1
Product: CCN(CC)CCOC(=O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
In similar manner substituting diethylethanolamine for the dimethylethanolamine, there is obtained β-N,N-diethylaminoethyl (5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)carboxylate.
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[N:12]3[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[C:17]1([C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([OH:2])=[CH:24][CH:23]=4)=[N:9][N:10]=3)[CH:13]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(Cc2nnc3ccc(-c4ccccc4)cn23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cc2nnc3ccc(-c4ccccc4)cn23)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(4-Methoxybenzyl)-6-phenyl-[1,2,4]triazolo[4,3-a]pyridine (0.057 g, 0.18 mmol) was dissolved in dichloromethane (2.5 mL) then cooled to 0° C. A 1M solution of boron tribromide (0.72 ml, 0.72 mmol) in dichloromethane was added slowly. The reaction mixture was stirred at 0° C. for 2 hours. A precipitate was present in the reaction mixture. The reaction was quenched with ice chips and stirred overnight at room temperature. A solid remained in the mixture. The reaction mixture was diluted with dichloromethane/methanol to give a clear mixture then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The sample was purified by preparative TLC eluting with 7% methanol in dichloromethane which afforded 4-((6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenol as an off-white solid
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.C([O-])(=O)C.[K+].[CH:28]1[CH2:32][CH2:31][CH2:30][CH:29]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.CN(C)C=O>[CH:32]1([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:3]=2)[CH2:31][CH2:30][CH:29]=[CH:28]1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: C1=CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(C2C=CCC2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To N,N-dimethylformamide 1 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.20 g were added potassium acetate 0.16 g, tetrabutylammonium chloride 0.15 g, cyclopentene 0.24 mL, palladium acetate 3.1 mg and triphenylphosphine 3.6 mg, and it was stirred under nitrogen atmosphere at room temperature for 17 hours. Ethyl acetate and 10% citric acid aqueous solution were added to the reaction mixture. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:toluene=5:1] to give tert-butyl 4-(2-cyclopenten-1-yl)-2-(4-fluoroanilino)benzoate 73 mg of yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH:11]=[O:12].[BH4-].[Na+].Cl>COCCOCCOC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: CCCCC[C@@H](CCC=O)OC1CCCCO1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCCCC[C@@H](CCCO)OC1CCCCO1
Reaction time: 4 h

Procedure:
A solution of (4S)-4-(2-tetrahydropyranyloxy)-nonanal (43.5 g., 0.18 mole) in diglyme (125 ml.) is treated with sodium borohydride (3.8 g., 0.10 mole). The temperature rises to 45° with the resulting exothermic reaction. The solution is stirred 4 hours, acidified with concentrated hydrochloric acid, and concentrated on the rotary evaporator. Water is added to the residue and the oily product is taken up in ether; washed with water and brine and dried over sodium sulfate. Evaporation of the ether leaves (4S)-4-(2-tetrahydropyranyloxy)-1-nonanol as a colorless oil to be used in the next step without further purification.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl:24][CH2:25][CH2:26][C:27](Cl)=[O:28].CO>C(Cl)Cl>[Cl:24][CH2:25][CH2:26][C:27]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1)=[O:28]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)CCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(N2CCN(C(=O)CCCl)CC2)cc1
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
1-(4-Methoxyphenyl)piperazine dihydrochloride (1.85 g, 6.976 mmol) was dissolved in methylene chloride. After adding triethylamine (1.9 mL, 13.952 mmol) dropwise at 0° C. and then dissolving, the mixture was stirred for 30 minutes. After adding 3-chloropropionyl chloride (0.67 mL, 6.976 mmol), the reaction solution was stirred at room temperature for 1 hour. After adding methanol, the reaction solution was extracted with methylene chloride. The organic layer was dried with desiccant and then filtered. The filtrate was concentrated and purified by column chromatography (EtOAc/hexane, 4:1). A target compound (1.76 g, 6.224 mmol, 89.3%) was yielded as white solid.
Reaction SMILES: [CH3:1][C:2]([S:5](Cl)=[O:6])([CH3:4])[CH3:3].Cl.[NH2:9][C:10]1([C:13]#[N:14])[CH2:12][CH2:11]1.C(N(C(C)C)C(C)C)C>ClCCl.CN(C1C=CN=CC=1)C>[C:13]([C:10]1([NH:9][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH2:12][CH2:11]1)#[N:14]
Reactant: N#CC1(N)CC1
Reactant: CC(C)(C)S(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)S(=O)NC1(C#N)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
2-methylpropane-2-sulfinic chloride (1.0 ml, 8.4 mmol) was added to a stirring solution of 1-aminocyclopropanecarbonitrile hydrochloride (1 g, 8 mmol) in dichloromethane (21 ml) and N-ethyl-N-isopropylpropan-2-amine (3.0 ml, 17 mmol) at 0° C. DMAP (10 mg, 0.084 mmol) was added and the reaction was allowed to stir 2 h at rt. The mixture was diluted with dichloromethane and washed with sat NH4Cl aq, and sat NaCl aq. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product N-(1-cyanocyclopropyl)-2-methylpropane-2-sulfinamide (1.5 g, 8.1 mmol, 95% yield) as a sticky yellow solid consistent by LCMS. LC-MS retention time: 1.40 min; m/z (MH+): 187. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1N)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]>CN(C)C=O.C(OCC)C>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][CH:24]=1)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc2c(Oc3cc(C)ccc3N)cccc2[nH]1
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cc2c(Oc3cccc(C)c3)cccc2[nH]1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl nitrite (0.428 ml, 3.609 mmol) is dissolved in 5 ml of dimethylformamide and heated to 65° C. A solution of 135 (1.1 g, 3.609 mmol) in 5 ml of dimethylformamide is added dropwise and the mixture is stirred of additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (930 mg of a brown oil) is further purified by flash-chromatography (hexane/ethyl acetate 7:3).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[N:3]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[NH2:1][C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27]3[CH:28]=[CH:29][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:25][CH:26]=3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(NC2CCCCC2)c2cc(Br)ccc2n1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Product: CC(=O)Nc1ccc(-c2ccc3nc(N)nc(NC4CCCCC4)c3c2)cc1
Yield: 95 %

Procedure:
This compound was synthesized from the product of example 20 and 4-acetamidophenyl-boronic acid, in 95% yield, using the procedure described for example 7, and was characterized by its mass spectrum as follows: MS (m/z): 376 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[C:15]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:13])[N:8]=[C:7]1CCCCCC)[CH3:2]>[Pd]>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([CH2:18][CH2:19][CH2:14][CH2:15][CH2:16][CH3:17])[N:6]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:13])[N:8]=[CH:7]1)[CH3:2]
Reactant: CCCCCCc1nc(NC(=O)c2cccc([N+](=O)[O-])c2C(=O)OCC)cn1CC(=O)OCC
Agent: [Pd]
Product: CCCCCCC(C(=O)OCC)n1cnc(NC(=O)c2cccc(N)c2C(=O)OCC)c1

Procedure:
A mixture of 5.1 g of -hexyl-4-{[(3-nitro-2ethoxycarbonylphenyl)carbonyl]amino}imidazole-1-acetic acid ethyl ester and 2.1 g of 5% palladium-on-carbon were hydrogenated in the presence of 150 ml of methanol until consumption of hydrogen ceased. The catalyst was removed by filtration and the filtrate concentrated in vacuo to provide 4.7 g of the desired subtitled intermediate. NMR.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[O:5].[CH3:27]OC(OC)N(C)C.CN(C=O)C.C(=O)([O-])O.[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH3:26][O:25][C:17]1[C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:27]=[N:1]2)=[CH:15][CH:16]=1
Reactant: CCCCCOc1c(OC)ccc(C(=O)NCCc2ccncc2)c1N
Reactant: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccncc3)cnc12
Temperature: 130 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
2-Amino-4-methoxy-3-pentyloxy-N-(2-pyridin-4-ylethyl)benzamide (100 mg, 0.280 mmol) obtained in Example 2-61, dimethyl formamide dimethyl acetal (0.19 ml, 1.4 mmol) and DMF (0.5 ml) were mixed, and p-toluene sulfonate monohydrate (2 mg, 0.011 mmol) was added to this solution. The mixture was stirred at 130° C. for 5 hours, and ethyl acetate (15 ml) and saturated aqueous sodium hydrogencarbonate solution (15 ml) were added to separate the organic layer. The organic layer was washed with saturated bnne (15 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (chloroform/methanol=25/1) to give 7-methoxy-8-pentyloxy-3-(2-pyridin-4-ylethyl)-3H-quinazolin-4-one (57 mg, 55%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Reactant: OCc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4ccc(F)cc4)cc3=O)ccc2nn1C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (500 mg), (4-fluorophenyl)methanol (494 mg) and triphenylphosphine (1.54 g) in tetrahydrofuran (40 ml) was added bis(2-methoxyethyl)azodicarboxylate (1.38 g) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (712 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:24]([OH:26])=[O:25]>>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:21]([F:20])=[C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCOc1ccc(C(=O)O)cc1F
Reactant: CCCCCCCC(C)C(=O)c1ccc(O)cc1F
Product: CCCCCCCC(C)C(=O)c1ccc(-c2c(C(=O)O)ccc(OCCCCCC)c2F)cc1F

Procedure:
The same procedure as in Example 20 was repeated, except that (+)-3-fluoro-4-(2-methylnonanoyl) phenol was used instead of (+)-3-fluoro-4-(2-methyloctanoyl) phenol in Example 20 and 3-fluoro-4-hexyloxy benzoic acid was used instead of 3-fluoro-4-heptyloxy benzoic acid in Example 20, to obtain an objective compound having the aforementioned physical and chemical properties.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][CH2:16][NH2:17].CCN(CC)CC>C1COCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:15][CH2:16][NH:17][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(CCNC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 107.3 %

Procedure:
Benzoyl chloride (0.922 g, 6.61 mmol) was added to a solution of 3-methoxyphenethylamine (1.000 g, 6.61 mmol) and Et3N (2.8 ml, 19.8 mmol) in anhydrous THF (30 ml) at rt under N2. The resulting suspension was stirred at rt under N2 for 20 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 1.811 g of white solid. Purification by flash chromatography, eluting with hexane:EtOAc (7:3) gave 1.689 g (100% yield) of white solid.