Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4].[N+:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])([O-:14])=[O:13]>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[C:9]1[C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cccc1CC
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CCCCn1c(CC)ccc1C(=O)c1cccc([N+](=O)[O-])c1
Yield: 27.5 %

Procedure:
A solution of 19 g (160 mmol) of 1-butyl-2-ethylpyrrole in 300 ml of toluene was treated with 38 g (200 mmol) of m-nitrobenzoyl chloride. The reaction mixture was refluxed under nitrogen atmosphere for 18 hours, cooled and purified by column chromatography on 1 Kg of deactivated alumina (containing 3% water), using hexane-acetone (90:10) as eluant. There were obtained 13.2 g (35%) of 1-butyl-2-(3'-nitrobenzoyl)-5-ethylpyrrole, the title compound, as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[CH:8]=2)[N:3]=1.[NH3:22]>>[Cl:1][C:2]1[N:11]=[C:10]([NH2:22])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[CH:8]=2)[N:3]=1
Reactant: N
Reactant: Fc1ccc(Oc2ccc3nc(Cl)nc(Cl)c3c2)c(F)c1
Product: Nc1nc(Cl)nc2ccc(Oc3ccc(F)cc3F)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound (1F) (21 g, 0.06 mol) was suspended in ammonia (100 mL of 2.0 M solution in MeOH) and the solution formed after 30 min was stirred at room temperature for 18 h. The precipitate was filtered, the concentrated filtrate triturated with EtOAc, and the organic layers were combined to yield 21.5 g of 2-chloro-6-(2,4-difluorophenoxy)-quinazolin-4-ylamine (1G).
Reaction SMILES: [OH-:1].[K+].[O:3]1[CH2:8][CH2:7][CH:6]=[CH:5][C:4]1=[O:9].[CH3:10]I>O>[OH:3][CH2:8][CH2:7]/[CH:6]=[CH:5]\[C:4]([O:9][CH3:10])=[O:1]
Reactant: [OH-]
Reactant: CI
Reactant: O=C1C=CCCO1
Agent: [K+]
Solvent: O
Product: COC(=O)/C=C\CCO
Temperature: 20 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Potassium hydroxide (3.36 g, 60 mmoles) was added to a stirred solution of 5,6-dihydro-2H-pyran-2-one (4.9 g, 50 mmoles) in water (45 ml) at 5° C. The solution was allowed to warm to 20° C. and stirred for 21/2 hours then evaporated to residue in a vacuum. The residue was flushed with isopropanol (2×50 ml) and dried in a vacuum at 50° C. over P2O5. This solid was slurried in dry dimethylformamide (30 ml) and methyl iodide (34.2 g, 240 mmol) added. The slurry was stirred for 18 hours at 20° C. then quenched by the addition of ice (20 g). The mixture was extracted with diethyl ether (4×50 ml) and the extracts washed with aqueous sodium chloride (50 ml) and dried (Na2SO4). Solvent removal in a vacuum afforded methyl (Z)-5-hydroxy-2-pentenoate as a colourless oil (4.1 g, 63% yield). The oil was dissolved in dichloromethane (40 ml) with N,N-dimethylaminopyridine (0.1 g) and treated with acetyl chloride (2.75 g, 35 mmoles) in dichloromethane (10 ml) added over 5 minutes at 5° C. The resulting slurry was allowed to warm to room temperature then quenched by the addition of water (40 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (40 ml) and the organic extracts combined, washed with hydrochloric acid (0.5M, 2×50 ml) then water (2×50 ml), and dried (Na 2SO4). Solvent removal in a vacuum followed by Kugelrohr distillation afforded methyl (Z)-5-acetoxy-2-pentenoate as a colourless oil (4.1 g, 76%) b.p. 75° C./0.1 mbar (Found: C, 55.60, H, 7.00 C8H12O4 requires C, 55.80; H, 7.00%).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][CH2:9][O:8]1.[OH-].[Na+]>O.CO>[O:8]1[CH2:9][CH2:10][CH2:11][O:12][CH:7]1[CH2:6][CH2:5][CH2:4][C:3]([OH:13])=[O:2]
Reactant: COC(=O)CCCC1OCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCC1OCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[1,3]Dioxan-2-yl-butyric acid methyl ester (6.8 g, 0.036 mol) was added to a stirred solution of sodium hydroxide (1.87 g, 0.047 mol) in water (30 ml) and methanol (30 ml). The mixture was stirred for 18 h at room temperature and then the solvent evaporated. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml) and cooled to 0° C. The mixture was acidified with hydrochloric acid (1M) to pH 2 and the layers separated. The aqueous layer was further extracted with cold ethyl acetate (100 ml) and the combined organic layers washed with brine (100 ml) and then dried (Na2SO4). The solvents were evaporated and the crude solid (5.56 g) was used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OC(CO)CN1c1ccc(I)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of iodo-alcohol 104 (25.2 g, 74.8 mmol) in methylene chloride (CH2Cl2, 150 mL) was treated with triethylamine (TEA, 15.15 g, 20.9 mL, 150 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled to 0-5° C. before methanesulfonyl chloride (MsCl, 10.28 g, 6.95 mL, 89.7 mmol, 1.2 equiv) was dropwise introduced into the reaction mixture at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 1 h under N2. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was quenched with H2O (100 mL) and CH2Cl2 (100 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (5R)-methanesulfonic acid 3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester 105 (30.71 g, 98.9% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. C11H11FINO5S, LCMS (EI) m/e 416 (M++H).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14])([O-:10])=[O:9].[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)#[N:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:18][C:17]1[CH:16]=[CH:15][C:13]([NH:14][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([C:19]#[N:20])=[CH:22][CH:23]=2)=[CH:12][C:11]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 1237.4 %

Procedure:
Triethylamine (23 ml) was added to a suspension of 3-nitro-4-methylaniline (0.8 g), 4-cyanobenzoyl chloride (13.1 g), 4-dimethylaminopyridine (0.8 g) in methylene chloride (200 ml) which had been cooled to 0° C. The reaction mixture was allowed to warm to ambient temperature and was stirred for 5 hours. The mixture was partitioned between methylene chloride and 0.5M hydrochloric acid solution. The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The residue was triturated under isohexane and the resulting solid was isolated and dried under vacuum at 55° C. to yield N-(4-methyl-3-nitrophenyl)-4-cyanobenzamide (18.3 g); NMR: 2.5 (s, 3H), 7.49 (d, 1H), 7.96 (m, 1H), 8.05 (d, 2H), 8.12 (d, 2H), 8.51 (d, 1H), 10.77 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:8])[CH2:4][C:5](N)=[O:6].C=C=[O:11]>>[Cl-:1].[Cl:1][CH2:2][C:3](=[O:8])[CH2:4][C:5]([O-:11])=[O:6]
Reactant: C=C=O
Reactant: NC(=O)CC(=O)CCl
Product: O=C([O-])CC(=O)CCl
Product: [Cl-]
Yield: 92 %

Procedure:
In a preferred embodiment of the invention, the yield of the 4-chloroacetoaceticacid ester, 4-chloroacetoaceticacid amide or 4-chloroacetoaceticacid imide is at least 90%, based on the total amount of ketene provided in step (a). More preferably, the yield is above 92% or above 95%. Preferably, the yield of 4-chloroacetoacetate chloride obtained in the first reaction step is more than 90%, preferably more than 95% or more than 98%. Preferably, the conversion of chlorine is at least 95%, more preferably at least 98% or at least 99.5%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:13][CH2:14][CH3:15].C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31](Cl)=[O:32].[H-].[Na+].[H][H]>C(OCC)(=O)C>[C:20]([O:19][C:17]([N:16]1[C@@H:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=2[CH3:1])[C:31](=[O:32])[CH2:30]1)=[O:18])([CH3:22])([CH3:21])[CH3:23]
Reactant: [H][H]
Reactant: CCCC[C@@H](CNc1cccc(C)c1C)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCC[C@H]1CN(c2cccc(C)c2C)C(=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of the product from Step C (8.50 g, 26.5 mmol) in ethyl acetate (250 mL) was vigorously stirred at 0° C. with saturated sodium bicarbonate (150 mL). Chloroacetyl chloride (2.33 mL, 29.1 mmol) was added, and the reaction stirred at ) 0° C. for 1 h. The layers were separated, and the ethyl acetate phase was washed with saturated brine, and dried over magnesium sulfate. The crude product was dissolved in DMF (300 mL) and cooled to 0° C. under nitrogen. Sodium hydride (1.79 g, 60% dispersion in oil, 44.9 mmol) was added portionwise to maintain moderate hydrogen evolution. After 30 min, an additional amount of sodium hydride was added (0.8 g). The reaction was stirred another 30 min, then quenched with saturated ammonium chloride. The DMF was distilled in vacuo, and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, and dried over magnesium sulfate. The crude product was chromatographed on silica gel with 20-30% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[F:19][C:20]([F:33])([F:32])[C:21]1[S:25][C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:23][CH:22]=1>>[CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:29]1[CH2:30][CH2:31][N:26]([C:24]2[S:25][C:21]([C:20]([F:33])([F:19])[F:32])=[CH:22][N:23]=2)[CH2:27][CH2:28]1)=[O:9])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Yield: 50 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropylsulfanyl-5-methanesulfonyl-benzoic acid (Example A22) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the tide compound as a white foam (yield 50%). MS (m/e): 494.4 (M+H+, 100%).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].NC[C:17]1[CH:18]=[C:19]([Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[O:20][CH:21]=1.[CH2:29]([N:31](CC)CC)C>O1CCCC1>[C:1]([NH:31][CH2:29][C:18]1[CH:17]=[CH:21][O:20][C:19]=1[Si:22]([CH2:23][CH3:24])([CH2:25][CH3:26])[CH2:27][CH3:28])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC[Si](CC)(CC)c1cc(CN)co1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)NCc1ccoc1[Si](CC)(CC)CC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Dodecanoyl chloride (109 mg, 0.49 mmol) was added to a solution of 4-aminomethyl-2-triethylsilylfuran (Compound 2, 70 mg, 0.33 mmol) and triethylamine (69 microliter, 0.49 mmol) in tetrahydrofuran (3 ml) at room temperature. After stirring at room temperature overnight (ca. 15 hours), most of the solvent was evaporated and the residue was purified by chromatography on preparative silica thin layer plates (developed with 50% ethyl ether/hexane) to give the title amide as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:22]3[CH:23]=[CH:24][O:20][CH:21]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Reactant: OB(O)c1ccoc1
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(-c3ccoc3)cc21

Procedure:
Prepared from 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester and furan-3-boronic acid using an analogous procedure to that of Preparation 161. MS: [M+H]+=315.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[Cl:20][C:21]1[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:20][C:21]1[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=2)[CH:8]=1)=[O:24]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c(Cl)c1
Yield: 69.2 %

Procedure:
2-Chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-4-(methylsulfonyl)benzamide was prepared in a similar manner as described herein from 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), 2-chloro-4-(methylsulfonyl)benzoic acid, (0.03 g, 0.13 mmol), HATU (0.05 g, 0.13 mmol), DIPEA (0.025 mL, 0.13 mmol) and DMF (1 mL). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.030 g, 69%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.20 (t, 1H), 8.02 (d, 1H), 7.92 (dd, 1H), 7.83 (d, 1H), 7.69 (d, 1H), 7.62 (d, 1H), 7.48 (d, 1H), 7.41 (t, 1H), 7.31 (dd, 1H), 7.23 (d, 1H), 4.46 (d, 2H), 3.30 (s, 3H). MS: m/z 508.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:37]=[C:5]2[N:6]([CH2:33][C:34](=O)[CH3:35])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Cl.[NH2:39][O:40][CH3:41].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:41][O:40]/[N:39]=[C:34](/[CH3:35])\[CH2:33][N:6]1[C:7](=[O:32])[C:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][C:29](=[O:31])[O:28][N:27]=3)=[CH:16][CH:15]=2)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=[C:2]([CH3:1])[N:37]=[C:5]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(C)=O)c2nc(C)nn12
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(C)=N\OC)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 7.6 %

Procedure:
A mixture of 2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), (aminooxy)methane hydrochloride (0.67 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.016 g, 8%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH2:15]([O:17][C:18](=[C:27]=[O:28])[CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16].C(N(CC)CC)C>O1CCCC1>[C:21]1([N:20]([CH2:19][C:18](=[C:27]=[O:28])[O:17][CH2:15][CH3:16])[C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([NH:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=C=O)CNc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=C=O)CN(C(=O)c1ccc(NC)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 24.7 g (0.115 mol) of 4-methylamino-3-nitro-benzoic acid chloride and 22.3 g (0.115 mol) of N-(2-ethoxy-carbonylethyl)-aniline in 300 ml of tetrahydrofuran, 13.1 g (0.13 mol) of triethylamine were added dropwise in 15 minutes, with stirring, at room temperature. After 2 hours stirring the solvent was distilled off in a water-jet vacuum and the residue was mixed with 700 ml of water with stirring. The mixture was extracted 3 times with 200 ml of dichloromethane, the organic extract was washed twice with 200 ml of 2N hydrochloric acid and twice with 300 ml of water and dried over sodium sulphate. The solvent was then distilled off and the oily product thus obtained was purified by column chromatography (1 kg silica gel; eluant: petroleum ether/ethyl acetate=2:1). Yield: 35.0 g (82% of theory), Rf value: 0.28 (silica gel; dichloromethane/ethanol=50:1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C@@H:8]2[C@H:12]([OH:13])[C@@H:11]([OH:14])[CH2:10][NH:9]2)=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[OH:13][C@@H:12]1[C@@H:11]([OH:14])[CH2:10][N:9]([C:26](=[O:27])[CH2:25][NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:19])[CH3:20])[C@@H:8]1[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=1
Reactant: COc1ccc(C[C@H]2NC[C@H](O)[C@H]2O)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(C[C@@H]2[C@H](O)[C@@H](O)CN2C(=O)CNC(=O)OC(C)(C)C)cc1
Yield: 96.3 %

Procedure:
Following the procedure as described in Example 24, except using the material from Example 39 (432 mg, 1.935 mmol), 2-(tert-butoxycarbonylamino)acetic acid (486.1 mg, 2.77 mmol), 1-hydroxy-7-azabenzotriazole (134.0 mg, 0.984 mmol), CH2Cl2 (20 mL), N-methylmorpholine (1.1 mL, 10.01 mmol), and EDC (560.5 mg, 2.92 mmol), 709.1 mg (96%) of the title compound is obtained as a white solid. Purification is done by BIOTAGE® Silica gel chromatography on a 25 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 100% EtOAc/Hexanes over 12 column volumes. LC/MS (Condition A): ret. T=3.07 min, (M+Na) 403.20.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([C:8](N(OC)C)=[O:9])[CH2:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl>O1CCCC1>[F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([CH:8]=[O:9])[CH2:4][CH2:3]1
Reactant: CON(C)C(=O)C1CCC(F)(F)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=CC1CCC(F)(F)CC1
Temperature: -70 °C
Reaction time: 0.58 h
Yield: 115.1 %

Procedure:
A mixture of 4,4-difluoro-N-methoxy-N-methylcyclohexane-1-carboxamide obtained in Example 2a (1.7 g, 8.21 mmol) and tetrahydrofuran (60 ml) was cooled to −70° C., a 1.0 M diisobutylaluminum hydride/toluene solution (9.85 ml, 9.85 mmol) was added, and the reaction mixture was stirred at −60° C. for 35 minutes. A 1.0 M diisobutylaluminum hydride/toluene solution (5 ml, 5 mmol) was further added at −65° C., and the reaction mixture was stirred at −70° C. for two hours. A 2 N aqueous hydrochloric acid solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off to give a crude product of the title compound (1.4 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:20]([O:24][C:25](=[O:36])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]O)=[CH:29][CH:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:13][CH2:14][C:15]([F:16])([F:18])[F:17])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:34][CH2:33][C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:36])=[CH:32][CH:31]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)OCC(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)cc1
Product: COC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC(F)(F)F

Procedure:
3-[4-(2-{4-tert-Butoxycarbonylaminophenyl}ethoxy)phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid methyl ester was synthesized using the same method as in Example 62 (a) from 3-(4-hydroxyphenyl)-2-(2,2,2-trifluoroethoxy)propanoic acid methyl ester and 4-(2-hydroxyethyl)phenylcarbamic acid tert-butyl ester(described in Example 38b.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C(N(CC)CC)C.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC>O1CCOCC1>[N:10]1[CH:9]=[CH:8][N:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=12
Reactant: Ic1ccc2nccn2c1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: c1ccn2ccnc2c1
Temperature: 90 °C

Procedure:
The obtained 2-[4′-(2″-hydroxyethoxy)]phenyl]-6-iodoimidazo[1,2-a]pyridine was dissolved in dioxane, and triethylamine is added thereto. Then, bis(tributyltin) and a catalytic amount of tetrakis-triphenylphosphine palladium are added thereto. This reaction mixture is heated at about 90° C. and reacted for about 24 hours, and then a solvent is distilled off and chromatographic purification is performed to obtain 6-tributylstannyl-2-[4′-(2″-hydroxyethoxy)]phenyl]imidazo[1,2-a]pyridine as the target compound (FIG. 2-2, Step 1). The amount of bis(tributyltin) to be used in this instance may be an amount satisfying a condition where it is excessive relative to the reaction substrate, specifically, it is about 1.5 times in molar ratio relative to the reaction substrate 2-[4′-(2″-hydroxyethoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine.