Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[CH:15]=[N:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:22]1[N:26]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1)CCC>>[F:16][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[N:26]3[CH:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]3=[N:24][CH:23]=2)=[CH:7][C:6]=1[C:8]1[CH:15]=[N:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1ccncc1-c1cc(Br)ccc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: N#Cc1ccncc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-(5-Bromo-2-fluorophenyl)isonicotinonitrile (40 mg, 0.14 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.18 mmol) by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 3% methanol, then recrystallisation from toluene/isohexane, gave 3-[2-fluoro-5-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)phenyl]isonicotinonitrile as a yellow solid: δH (400 MHz, CDCl3) 7.30 (1H, d, J 7), 7.51 (1H, t, J 9), 7.67-7.73 (3H, m), 8.13 (1H, s), 8.87 (1H, d, J 5), 8.96-8.98 (2H, m); m/z (ES+) 384 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>ClCCl>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[O:20])=[CH:12][C:11]=1[C:9]1[O:10][C:4]2[C:5]([N:8]=1)=[N:6][CH:7]=[C:2]([NH:1][C:34](=[O:35])[O:36][CH:37]([CH3:39])[CH3:38])[CH:3]=2
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1cnc2nc(-c3cc(NC(=O)c4ccco4)ccc3Cl)oc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)Nc1cnc2nc(-c3cc(NC(=O)c4ccco4)ccc3Cl)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-[6-amino-[1,3]oxazolo[4,5-b]pyridin-2-yl]-4-chlorophenyl)furan-2-carboxamide (1-15) (100 mg, 0.28 mmol, 1.00 equiv), triethylamine (85 mg, 0.84 mmol, 2.98 equiv), chloro(propan-2-yloxy)methanone (70 mg, 0.57 mmol, 2.03 equiv) in dichloromethane (15 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 10 mg (8%) of propan-2-yl N-[2-[2-chloro-5-(furan-2-amido)phenyl]-[1,3]oxazolo[4,5-b]pyridin-6-yl]carbamate (76) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[OH:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c([N+](=O)[O-])c1
Temperature: 120 °C
Yield: 93.4 %

Procedure:
A mixture of 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (20 g, 91 mmol), 2,4-difluorophenol (11.87 g, 91 mmol) and potassium carbonate (12.6 g, 91 mmol) in DMSO (90 mL) was heated at 120° C. for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1:1 ethyl acetate/hexanes) to provide the title compound (28 g, 89% yield).
Reaction SMILES: [C:1](=[O:12])([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])N.[CH2:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1](=[O:12])([O:21][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CCCCCO
Reactant: CC(C)CCCCCOC(N)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)CCCCCOC(=O)OCCCCCC(C)C
Temperature: 270 °C
Yield: 92.33 %

Procedure:
30.94 g of isooctyl carbamate, 48.90 g of isooctanol, 0.40 g of triphenylphosphine and 2.0 ml of a 20% strength solution of diisobutyl-aluminium hydride in toluene were warmed together, whilst stirring. The mixture started to boil at about 165° C. The mixture was now heated in such a way that a continuous reflux of isooctanol was set up in a Vigreux column (jacket length 30 cm) fitted on the reaction vessel. The temperature was raised continuously to 270° C. over a period of 7 hours; after that time 2.78 g (91.3% of theory) of NH3 had been separated off and 24.95 g of liquid and a little solid had been distilled off (isooctanol, urethane and urea). The mixture was then subjected to fractional distillation. A fraction of 4.35 g with a boiling point14 of 81.5 (isooctanol) and a fraction of 46.96 g with a boiling point~ 0.05 of 98-102 (diisooctyl carbonate) resulted. Yield 92.33%, based on urethane employed.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([N:12]2[C@@H:19]3[C@@H:14]([CH2:15][CH2:16][NH:17][CH2:18]3)[CH2:13]2)[CH:3]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([N:46]2[N:50]=[CH:49][CH:48]=[N:47]2)[C:38]=1[C:39](O)=[O:40].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([N:46]2[N:50]=[CH:49][CH:48]=[N:47]2)[C:38]=1[C:39]([N:17]1[CH2:16][CH2:15][C@@H:14]2[C@@H:19]([N:12]([C:4]3[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[N:5]=3)[CH2:13]2)[CH2:18]1)=[O:40]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(C(F)(F)F)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-n4nccn4)C[C@@H]32)nc(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[8-(6-methyl-2-trifluoromethyl-pyrimidin-4-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 9) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 3-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. Additionally, the reaction time was shortened to 30 minutes. MS (ESI) mass calcd. for C21H19F4N7O, 461.42; m/z found 462.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.89-7.60 (m, 3H), 7.57-7.27 (m, 1H), 7.20-6.99 (m, 1H), 6.90-6.55 (m, 1H), 4.85 (5, br, 0.35H), 4.50-3.12 (m, 7H), 2.97-2.57 (m, 1.65H), 2.44-2.04 (m, 7H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][CH2:5][C@H:6]([NH:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][OH:8].Cl[C:30]1[C:34]2[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=2[O:32][N:31]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]2[O:32][N:31]=[C:30]([O:8][CH2:7][C@@H:6]([NH:9][C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][S:4][CH3:3])[C:34]=2[CH:35]=1
Reactant: CSC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1ccc2onc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSC[C@@H](COc1noc2ccc(Cl)cc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 77.6 %

Procedure:
To a suspension of 0.44 g of 60% (w/w) sodium hydride in 6 ml of N,N-dimethylformamide is dropwise added 15 ml of an N,N-dimethylformamide solution of 4.0 g of (R)-3-methylthio-2-tritylamino-1-propanol over 15 minutes with ice-cooling, and the temperature is gradually elevated to 80° C., after which this is added to a solution of 2.07 g of 3,5-dichloro-1,2-benzoisoxazole in 10 ml of N,N-dimethylformamide. They are subjected to reaction at the same temperature for one hour. After cooling, water and ethyl acetate are added and shaken, and the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluant:n-hexane:ethyl acetate=20:1], to obtain 4.4 g of oily (R)-5-chloro-3-(3-methylthio-2-tritylaminopropoxy)-1,2-benzoisoxazole.
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[C:28](Cl)(=[O:34])[CH2:29][CH:30]=[CH:31][CH2:32][CH3:33]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:34])[CH2:29][CH:30]=[CH:31][CH2:32][CH3:33])[CH2:24][CH2:23]2)[N:9]=1
Reactant: CCC=CCC(=O)Cl
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC=CCC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reaction time: 0.33 h
Yield: 47.3 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture was stirred for 20 minutes. There was then added 0.8 g of 3-hexenoyl chloride, after which the mixture was stirred at room temperature for 15 hours. The resulting crystals were collected by filtration, washed with water and recrystallized from ethanol, to give 1.10 g of the desired Compound No. 7 in the form of pale yellow powdery crystals melting at 197.5°-198.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[OH:16])[CH:11]=[O:12])=[CH:4][C:3]=1[S:17]([CH3:20])(=[O:19])=[O:18].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:11]=[O:12])[CH:13]=[CH:14][C:15]=2[O:16][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:4][C:3]=1[S:17]([CH3:20])(=[O:18])=[O:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CS(=O)(=O)c1cc(-c2cc(C=O)ccc2O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1-c1ccc(F)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of 3-(4-fluoro-3-(methylsulfonyl)phenyl)-4-hydroxybenzaldehyde (28) (315 mg, 1.1 mmol, 1 eq.) in DMF (10 mL) was added Cs2CO3 (715 mg, 2.2 mmol, 2 eq.) and t-butyl 2-bromoacetate (236 mg, −1.2 mmol, 1.2 eq.). After stirring at room temperature, for 16 h, the solvent was removed in vacuo, and the resultant residue was extracted between EtOAc and H2O (3×20 mL). The organic layer was dried (Na2SO4), and concentrated in vacuo. The resultant residue was purified by column chromatography (eluent: PE:EA=1:1) to give 250 mg (57%) of t-butyl 2-(2-(4-fluoro-3-(methylsulfonyl)phenyl)-4-formylphenoxy)acetate (29) as oil.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:15]C[CH:13](O)[CH2:12]1.C(OC(C)C)(C)C.O1CCOCC1>>[C:1]([O:9][CH:10]1[CH2:13][CH2:12][NH:11][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1
Reactant: OC1CCNC1
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: O=C(OC1CCNC1)c1ccccc1
Yield: 66 %

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (3.0 mmol), pyrrolidin-3-ol (3.6 mmol), Zn4(OCOCF3)6O (1.25 mol % in terms of mole number) and diisopropyl ether/1,4-dioxane (3/1) (5.0 ml) was heated to reflux for 46 hours, and as a result, pyrrolidin-3-yl benzoate was obtained at a yield of 66%. The yield of N-benzoylpyrrolidin-3-yl benzoate was 34%.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>[OH-].[Na+]>[CH:13]1([C:18]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCC1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)NCCC[C@H](NC(=O)C1CCCC1)C(=O)O
Temperature: 25 °C
Yield: 131.2 %

Procedure:
(L)-Arginine (32.8 g., 0.19 moles) was dissolved in 188 mL of 2 N sodium hydroxide. Cyclopentanoyl chloride (22.9 mL, 0.19 moles) were added dropwise to the mixture. The reaction mixture was maintained at about 25° C. for 2 hours. The mixture was then acidified to pH 1.5 with aqueous (4:1) hydrochloric acid. The precipitate which formed was separated by decantation. The solids were dissolved in 2 N sodium hydroxide to pH 7.5 and dried by lyophilization to furnish 67.4 g of N-cyclopentanoyl-(L)-arginine. The product was a white solid. Mass Spectrum: M+1 m/e 271.
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])([CH2:3][CH3:4])[CH3:2].C([Li])CCC.[CH3:16][C:17]1[N:18]=[C:19](S(C)=O)[O:20][CH:21]=1.O>O1CCOCC1>[CH:1]([N:5]([C:19]1[O:20][CH:21]=[C:17]([CH3:16])[N:18]=1)[C:6](=[O:10])[CH2:7][CH2:8][CH3:9])([CH2:3][CH3:4])[CH3:2]
Reactant: Cc1coc(S(C)=O)n1
Reactant: CCCC(=O)NC(C)CC
Agent: [Li]CCCC
Solvent: O
Solvent: C1COCCO1
Product: CCCC(=O)N(c1nc(C)co1)C(C)CC
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
N-s-Butyl-butyramide (0.99 g, 0.0069 m) in dry dioxan (10 ml) was cooled to 10° C. under nitrogen during the dropwise addition of a 1.445 M solution of n-butyl lithium (4.8 ml, 0.0069 m). The mixture was stirred for 15 minutes at 10° C. and then 4-methyl-2-methylsulphinyloxazole (1.0 g, 0.0068 m) in dry dioxan (10 ml) was added and the mixture allowed to warm to room temperature. It was stirred for 3 hours and then hydrolysed with water. The solvent was removed in vacuo and the ether extract of the residue was chromatographed on silica using ether. The resulting compound (title product) was distilled in vacuo as a colourless oil 0.95 g, b.p. 75°-76° C./0.5 mm.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].[Li]CCCC.[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[O:19]=[C:15]([N:5]1[C@@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:8][O:7][C:6]1=[O:9])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(=O)Cl
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: 0 °C
Yield: 104.6 %

Procedure:
A mechanically stirred, cooled (-78° C.) solution of the oxazolidinone of Step 5 (32.3 g, 250 mmol) in anhydrous THF (830 mL) was metalated with 163 mL (1.6M in hexane, 261 mmol) of n-BuLi and treated with freshly distilled butanoyl chloride (28.1 mL, 271 mmol). The reaction mixture was warmed to 0° C. and stirred for 0.5 h. Excess acid chloride was hydrolyzed by the addition of 1M aqueous K2CO3 (165 mL) followed by stirring the resultant two-phase mixture for 1 h at r.t. Volatiles were removed in vacuo and the product was extracted into CH2Cl2 (3×). The combined organic extracts were successively washed with H2O and brine, dried over MgSO4 and concentrated to give the title compound as a pale yellow oil (52.1 g, quantative). A portion of this crude product was purified by flash chromatography on silica with EtOAc:hexane 1:4 to give a colorless liquid.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([C:8]([OH:10])=O)[N:7]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([N:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[CH:36]=1>CN(C)C=O.CN(C)C(=O)C>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:28]=[C:27]([NH:26][C:8]([C:6]5[N:7]=[C:3]([CH2:1][CH3:2])[O:4][C:5]=5[C:11]([F:14])([F:13])[F:12])=[O:10])[CH:48]=[CH:47][CH:46]=4)=[CH:36][N:35]3[N:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: CCc1nc(C(=O)O)c(C(F)(F)F)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1nc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C(F)(F)F)o1
Yield: 48.8 %

Procedure:
In the same manner as in Example 18-4 and using 2-ethyl-5-(trifluoromethyl)-1,3-oxazole-4-carboxylic acid (314 mg, 1.50 mmol), tetrahydrofuran (7 mL), oxalyl chloride (143 μL, 1.65 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (309 mg, 1.00 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (244 mg, 49%) was obtained as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>O>[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To 2,3-dichloro-5-trifluoromethylpyridine (25 g) were added 1-BOC-piperazine (23.84 g), potassium carbonate (32.08 g), N,N-dimethylformamide (50 mL) and toluene (50 mL), and the mixture was stirred at 100° C. for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (45.71 g). To 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (11 g) were added palladium (II) acetate (0.726 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.692 g), potassium fluoride (15.06 g), methylboronic acid (7.88 g) and tetrahydrofuran (300 mL), and the mixture was refluxed under a nitrogen stream for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9.14 g). To 4-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9.14 g) were added 4N hydrogen chloride/ethyl acetate (26 mL) and chloroform (64 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and sodium hydrogen carbonate, and the mixture was extracted with chloroform. The solvent was evaporated to give the title compound (6.38 g).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[Br:25][CH2:26][CH2:27][CH2:28]Br>>[Br:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: BrCCCBr
Reactant: O=C(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccccc1
Product: O=C(c1ccc(OCCCBr)cc1)c1oc2ccccc2c1-c1ccccc1

Procedure:
Reaction of 2-(4-hydroxybenzoyl)-3-phenylbenzofuran with 1,3-dibromopropane according to the procedure of Example 4 gives 2-[4-(3-bromopropoxy)benzoyl]-3-phenylbenzofuran.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][CH3:22])=[S:20])=[CH:14][CH:13]=1.BrBr>>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]2[N:18]=[C:19]([NH:21][CH3:22])[S:20][C:16]=2[CH:17]=1
Reactant: CNC(=S)Nc1ccc(-c2nc3cc(C)ccn3c2C)cc1
Agent: BrBr
Product: CNc1nc2ccc(-c3nc4cc(C)ccn4c3C)cc2s1
Yield: 11.6 %

Procedure:
6-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)-2-methylaminobenzothiazole (0.46 g) was prepared in substantially the same manner as that of Example 36 from 3,7-dimethyl-2-[4-(3-methylthioureido)phenyl]-imidazo[1,2-a]pyridine (4.0 g) and bromine (2.08 g).
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8]([OH:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([O:5][CH3:6])=[O:4].CO[C:20](OC)([CH3:22])[CH3:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CO>C(Cl)Cl>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][CH:8]([CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[O:17][C:20]([CH3:22])([CH3:21])[O:1]1)=[O:4]
Reactant: COC(=O)C(O)CC(O)CC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CC(CC(=O)OC(C)(C)C)OC(C)(C)O1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 1-methyl 6-tert.-butyl 2,4-dihydroxyadipate (4.98 g, 20.01 mmol) in methylene chloride (2 dimethoxypropane (9.6 ml, 78 mmol) and pyridinium p-toluenesulfonate (2.01 g, 8 mmol) were added and stirred under reflux conditions for one hour, followed by further stirring at 40° C. for 3 hours while azeotropically removing methanol with methylene chloride. After concentration under reduced pressure, the residue was dissolved in ethyl acetate and poured in water. Then, the mixture was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:acetone=3:1) to give pure 2-methoxycarbonyl-4-tert.-butoxycarbonylmethyl-6,6-dimethyl-1,5-dioxane (4.89 g, 17.01 mmol). Yield, 85 %.
Reaction SMILES: [C:1]([C:9]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:17]([OH:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[OH:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ag]=O.C(Cl)(Cl)Cl>[C:1]([C:9]1[C:10](=[O:26])[C:11]2[C:16]([C:17](=[O:25])[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1c(-c2ccccc2)c(O)c2ccccc2c1O
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Product: O=C(C1=C(c2ccccc2)C(=O)c2ccccc2C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 500 ml conical flask, the above 2-benzoyl-1,4-dihydroxy-3-phenylnaphthalene (35 g, 103 mmol), silver oxide (23.8 g, 103 mmol) and chloroform (300 ml) were added and, after stirring at room temperature for 5 hours, the solid deposited in the solution was removed and the solution was concentrated to deposit a crystal.