Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:22][S:23]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.1 %

Procedure:
To 1 g (4.97 mmol) of tert-butyl 4-hydroxypiperidine-1-carboxylate diluted in 12.5 ml of anhydrous dichloro-methane are added dropwise at 0° C. 718 μl, of triethylamine (4.97 mmol), then 385 μL (4.97 mmol) methanesulfonyl chloride and finally 6 mg (49.6 μmol) of 4-dimethylamino-pyridine (DMAP). The solution is stirred at room temperature for 20 h, then water is added and the product is extracted several times with dichloromethane. The organic phases are combined, dried over magnesium sulfate, and concentrated to yield 1.39 g of tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate in the form of white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].C(N(CC)CC)C.Cl[C:16]1[C:21]([C:22]#[N:23])=[C:20]([NH:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)[N:29]=[CH:28]3)[N:19]=[CH:18][N:17]=1>C1COCC1>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][S:3][C:16]1[C:21]([C:22]#[N:23])=[C:20]([NH:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)[N:29]=[CH:28]3)[N:19]=[CH:18][N:17]=1)[CH3:7]
Reactant: N#Cc1c(Cl)ncnc1Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Reactant: CCOC(=O)CS
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CSc1ncnc(Nc2ccc3c(cnn3Cc3cccc(F)c3)c2)c1C#N

Procedure:
Ethyl thioglycolate (also referred to as mercapto-acetic acid ethyl ester) Compound 4f (0.57 g, 4.75 mmol) and triethylamine (0.78 mL, 5.54 mmol) were added to a solution of 4-chloro-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbonitrile Compound 4e (1.5 g, 3.96 mmol) in THF (20 mL) at RT under nitrogen. The reaction mixture was refluxed for 6 hours, then partitioned between ethyl acetate and water. The organic layer washed with aqueous 10% NH4Cl, water and brine, then dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (1% methanol/dichloromethane) to yield {5-cyano-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidin-4-ylsulfanyl}-acetic acid ethyl ester Compound 4g (0.83 g, 45%) as a solid. 1H NMR (400 MHz, DMSO) δ 9.99 (1H, br s), 8.42 (1H, s), 8.13 (1H, d), 7.82 (1H, d), 7.82 (1H, d, J=8.9 Hz), 7.43 (1H, dd, J=1.9 Hz & 8.9 Hz), 7.36-7.34 (1H, m), 7.11-7.02 (3H, m), 5.69 (2H, s), 4.15-4.10 (4H, m), 1.18 (3H, t); MS (ES+) m/z 463.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH-].[K+].[Cl:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]=1[C:26]([F:29])([F:28])[F:27].Cl>O.CN(C)C=O>[Cl:8][C:7]1[C:2]([NH:1][C:17]2[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]([C:26]([F:27])([F:28])[F:29])=[C:13]([Cl:12])[C:18]=2[N+:19]([O-:21])=[O:20])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Nc1ncc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
In 20 ml. of dimethylformamide, 1.63 g. of 2-amino-3,5-dichloropyridine was dissolved and 0.73 g. of powdery potassium hydroxide was added with stirring. After the addition, 3.06 g. of 2,4-dichloro-3,5-dinitrobenzotrifluoride was added during 10 minutes. The reaction was continued for about 2 hours. After the reaction, the reaction mixture was poured into water and acidified with conc. HCl and the product was extracted with methylene chloride. The extracted layer was washed with water and dehydrated and the solvent was distilled off and the product was separated by a silica gel column with an eluent of toluene and then the solvent was distilled off to obtain 1.38 g. of the object compound having the melting point of 64° to 65° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Ca+2].[I:18]Cl>CO.O>[I:18][C:3]1[CH:4]=[C:5]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: ClI
Reactant: Nc1ccc(-n2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CO
Product: Nc1ccc(-n2cncn2)cc1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-1,2,4-triazole (1.0 g, 6.25 mmol) in MeOH (10 mL) and water (10 mL) was added CaCO3 (1.2 g, 12.0 mmol), followed by a solution of iodine monochloride (1.2 g, 7.38 mmol) in MeOH (10 mL). The reaction mixture was stirred at r.t. for 1.5 h, and then partitioned between EtOAc (100 mL) and aqueous sat. Na2S2O3 (100 mL). The organic fraction was separated, washed with aqueous sat. Na2S2O3 (100 mL), then water (100 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-100% EtOAc/hexanes) gave the title compound (1.2 g, 67%). LCMS (ES+) 286.9 (M+H)+, RT 2.78 minutes (Method 5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].O[C@@H:24]1[CH2:28][CH2:27][O:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: O[C@@H]1CCOC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline in 6 ml acetonitrile are combined with 114 μl (R)-3-hydroxy-tetrahydrofuran and 370 mg triphenylphosphine. Then 234 μl diethyl azodicarboxylate are added and the reaction mixture is stirred overnight at ambient temperature. For working up the reaction mixture is filtered and the filtrate evaporated down in vacua. The crude product is purified by chromatography over a silica gel column with ethyl acetate/-methanol (95:5) as eluant.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27](C2SC(C3C=CC(C(O)=O)=CC=3)=NN=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]Br.Cl>CN(C)C=O>[O:23]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccc(-c2nnc(-c3ccc(O)cc3)s2)cc1
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccc(O)cc3)s2)cc1
Reactant: BrCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2nnc(-c3ccc(OCCCCCOc4ccccc4)cc3)s2)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a suspension of a mixture of methyl 4-[5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoate and 4-[5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid (2.0 g), potassium carbonate (14.6 g) and N,N-dimethylformamide (15 ml) was added 1,5-dibromopentane (10 ml) and the mixture was stirred at 100° C. (bath temperature) for 1.5 hours. The resulting mixture was neutralized by 0.1N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with n-hexane. The solid was collected by filtration and dried. To this compound was added phenol (1.43 g), potassium carbonate (2.10 g) and N,N-dimethylformamide (30 ml), and the mixture was stirred at 100° C. (bath temperature) for 20 hours. After cooling, the reaction mixture was poured into saturated sodium hydrogen carbonate aqueous solution. The resulting precipitate was collected by filtration, washed with water. To this compound was added tetrahydrofuran (20 ml), ethanol (20 ml) and 10% sodium hydroxide aqueous solution (2.6 ml). The mixture was refluxed for 1.5 hours. The reactor mixture was diluted with water, acidified with 1N hydrochloric acid (10 ml). The resulting precipitate was collected by filtration, washed with water, dried under reduced pressure to give 4-[5-[4-(5-phenoxy-n-pentyloxy) phenyl]-1,3,4-thiadiazol-2-yl]benzoic acid (2.47 g), that was used crude in the next reaction.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O=[C:15]([CH3:28])[CH2:16][O:17][C:18]1[CH:26]=[C:22]([C:23]([NH2:25])=[O:24])[C:21]([OH:27])=[CH:20][CH:19]=1.[H][H]>CO.[Pt]>[CH2:1]([NH:8][CH:15]([CH3:28])[CH2:16][O:17][C:18]1[CH:26]=[C:22]([C:23]([NH2:25])=[O:24])[C:21]([OH:27])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)COc1ccc(O)c(C(N)=O)c1
Reactant: [H][H]
Agent: [Pt]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(COc1ccc(O)c(C(N)=O)c1)NCc1ccccc1

Procedure:
55 g of benzylamine and 1.25 g of concentrated sulphuric acid are added to a solution of 104.5 g of 5-(2-oxopropoxy)salicylamide in 1000 ml of methanol and hydrogenated in the presence of 3.0 g of Pt/C-catalyst at room temperature and atmospheric pressure until 1 equivalent of hydrogen has been absorbed. The catalyst is filtered off, approximately 10 g of powdered calcium carbonate are stirred into the solution and the solution is filtered again and concentrated by evaporation. The oil remaining crystallises from isopropanol. Repeated recrystallisation from isopropanol yields 5-[2-(benzylamino)propoxy]salicylamide having a melting point of 102°-104°.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].[C:4](=O)([O-])[OH:5].[Na+].CS(C)=O.C([O:16][C:17]([CH3:56])([CH3:55])[C:18]([O:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([N:27]2[C:32](=[O:33])[C:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]#[N:48])=[CH:37][CH:36]=3)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]3[N:52]=[CH:53][CH:54]=[C:28]23)[CH2:23][CH2:22]1)=[O:19])(=O)C>C(OCC)(=O)C>[OH:16][C:17]([CH3:55])([CH3:56])[C:18]([O:20][C@H:21]1[CH2:22][CH2:23][C@H:24]([N:27]2[C:32](=[O:33])[C:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]4[NH:48][C:4](=[O:5])[O:2][N:3]=4)=[CH:37][CH:36]=3)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]3[N:52]=[CH:53][CH:54]=[C:28]23)[CH2:25][CH2:26]1)=[O:19]
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(=O)C(C)(C)OC(C)=O)CC2)c2ccnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(=O)C(C)(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogen carbonate (1.0 g) and dimethyl sulfoxide (4 mL) was stirred at 50° C. for 30 min, trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl 2-(acetyloxy)-2-methylpropanoate (0.67 g) was added, and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (4 mL). N,N′-Carbonyldiimidazole (0.15 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.083 g, 17%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][N:13]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:12](=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:24](Br)[CH:25]=[CH2:26].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH2:26]([C@H:11]1[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:14][N:13]([C@@H:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])[C:12]1=[O:23])[CH:25]=[CH2:24]
Reactant: C[C@H](c1ccccc1)N1C[C@@H](CO[Si](C)(C)C(C)(C)C)CC1=O
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1C(=O)N([C@H](C)c2ccccc2)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: -5 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
(4S)-4-(tert-Butyldimethylsilyloxy)methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine (333.5 g, 1.00 mol) and allyl bromide (90.9 mL, 1.05 mol) were dissolved in tetrahydrofuran (1.10 L). Lithium hexamethyldisilazide (1.0 M solution in tetrahydrofuran) (1.10 L, 1.10 mol) was added dropwise at −15° C., and the mixture was stirred at −5° C. for one hour. The reaction solution was extracted with a saturated ammonium chloride solution and ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. Thereafter, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to give 327 g of the title compound as a colorless syrup.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:10])[CH:8]=O.Cl.[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14][C:13]1=[O:21]>ClCCl.N1C=CC=CC=1>[CH3:6][N:7]([CH:10]=[C:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:12][C:13]1=[O:21])[CH3:8]
Reactant: O=C1Cc2cccnc2N1
Reactant: CN(C)C=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C1C(=O)Nc2ncccc21
Temperature: 2.5 °C
Reaction time: 0.17 h

Procedure:
Phosphorous oxychloride (1.93 mL, 3.17 mmol) is added slowly to a stirred solution of dimethylformamide (1.99 mL) and dichloromethane (3 mL) cooled to 0-5° C. After 10 min, a solution of the above 1,3-dihydropyrrolo[2,3-b]pyridine-2-one hydrochloride (6-aza-1,3-dihydroindol-2-one) (790 mg, 4.63 mmol), pyridine (1.5 mL) and dichloromethane (5 mL) is added over 5 min and the reaction is stirred at room temperature for 18 hr. The solvents are removed to yield crude 3-dimethylaminomethylene-1,3-dihydropyrrolo[2,3-b]pyridin-2-one.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([NH:15][CH3:16])=[O:14].C(N(C(C)C)C(C)C)C>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][CH3:16])=[O:14])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CNC(=O)c1cccc(N)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(Nc2ccnc(Cl)n2)c1
Temperature: 60 °C
Reaction time: 23 h
Yield: 88.2 %

Procedure:
To 2,4-dichloropyrimidine (250.0 mg, 1.678 mmol) and 3-amino-N-methylbenzamide (252 mg, 1.678 mmol) in 2-propanol (8390 μL) in a disposable sealed tube at RT was added N-ethyl-N-isopropylpropan-2-amine (585 μL, 3.36 mmol). The resulting reaction mixture was heated at 60° C. for 22 h, then to 70° C. for 23 h, then 80° C. for 3 days, cooled to RT, concentrated, purified using MPLC (5 g cartridge, 12 g column, 0 to 60% 90/10 CH2Cl2-MeOH in CH2Cl2) giving 3-(2-chloropyrimidin-4-ylamino)-N-methylbenzamide (389.0 mg).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:30])([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1)[CH:17]([F:19])[F:18]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:29]([CH:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][C:16]([F:15])([F:30])[CH:17]([F:18])[F:19])=[CH:22][CH:23]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1ccc(OC(F)(F)C(F)F)cc1
Agent: Cl
Product: CC(c1ccc(OC(F)(F)C(F)F)cc1)N1Cc2c(ccnc2Cl)C1=O
Yield: 75 %

Procedure:
The title compound is prepared in 75% yield (165 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine hydrochloride (155 mg, 0.57 mmol, Amine-29, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19](O)=[O:20])=[N:11][C:12]3[N:13]([N:16]=[CH:17][CH:18]=3)[C:14]=2[F:15])=[C:4]([F:22])[CH:3]=1.CC[N:25]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH2:25])=[O:20])=[N:11][C:12]3[N:13]([N:16]=[CH:17][CH:18]=3)[C:14]=2[F:15])=[C:4]([F:22])[CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1nc2ccnn2c(F)c1Nc1ccc(Br)cc1F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NC(=O)c1nc2ccnn2c(F)c1Nc1ccc(Br)cc1F
Reaction time: 0.5 h

Procedure:
A mixture of 6-(4-bromo-2-fluorophenylamino)-7-fluoropyrazolo[1,5-a]pyrimidine-5-carboxylic acid (1.00 equivalent), EDCI (1.50 equivalents), and HOBt (1.50 equivalents) in DMF is stirred for 30 minutes. NH4Cl (3.00 equivalents) is added followed by Et3N (2.50 equivalents). After 1 hour, the reaction mixture is diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer is dried (MgSO4) and concentrated. The product is purified by flash chromatography as necessary.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH2:12]=[O:13].Cl.[CH3:15]O>>[OH:1][C:2]1[C:7]([CH2:12][O:13][CH3:15])=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CO
Reactant: C=O
Reactant: CC(=O)c1cc(C)ccc1O
Agent: Cl
Product: COCc1cc(C)cc(C(C)=O)c1O
Temperature: 60 °C

Procedure:
A mixture of 2′-hydroxy-5′-methylacetophenone (1.0 g, 6.7 mmol) was treated with paraformaldehyde (0.18 g) and conc. hydrochloric acid (5 ml) and the mixture heated at 60° C. overnight. Upon cooling the mixture was extracted with toluene (3×30 ml) and the combined extracts were dried (Na2SO4) and the solvent removed to yield a yellow oil. The oil was treated with methanol (30 ml) and heated to reflux for 1 h. Upon cooling, the solution was evaporated to near dryness, and the residue chromatographed on a silica column, eluting with 0-10% ethyl acetate in petroleum ether. The purified product was obtained as an white powder (0.76 g)
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([C:9]1[CH2:13][CH2:12][C:11](=O)[CH:10]=1)([CH3:8])([CH3:7])[CH3:6].Cl>C(OCC)C>[CH2:1]([C:12]1[CH2:11][CH:10]=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[CH:13]=1)[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)CC1
Reactant: CC[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CCC1=CC(C(C)(C)C)=CC1
Temperature: 0 °C
Yield: 65 %

Procedure:
To a 200 ml three-neck flask equipped with a magnetic stirrer chip and a three-way cock, 50 ml of dehydrated diethyl ether and 59 ml (180 mmol) of diethyl ether solution of 3.0 M ethyl magnesium bromide were charged under a nitrogen atmosphere. In the ice-water bath, 21.4 g (155 mmol) of 3-tert-butylcyclopentenone was added dropwise over 1 hour. The resultant solution was stirred at room temperature for 16 hours, and then the reaction solution was poured into 100 ml of 3N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with 50 ml of ether. The obtained organic layers were combined, washed once with a saturated aqueous solution of sodium hydrogencarbonate, twice with water, and once with saturated brine, and dried over magnesium sulfate and distilled off under reduced pressure to obtain 15.3 g of a pale yellowy transparent solution. The yield was 65%. Identification was done by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][N:3]=1.OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>>[NH2:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)c(Cl)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 0.05 h
Yield: 26.2 %

Procedure:
To a 50 ml round-bottomed flask containing 2-amino-4,5-dichloropyridine (0.275 g, 1.65 mmol) and cooled into an ice-bath was added conc. H2SO4 (2.79 g). The reaction mixture was stirred for 3 min and then HNO3 (70%; 0.186 g) was dropwise added. The reaction mixture was stirred at 0° C. (ice-bath) for 7 min, then heated to 55° C. and stirred at this temperature for 1 h, allowed to cool to room temperature, diluted with ice-water (˜15 ml) and the pH was adjusted to ˜7.5 with 10% aqueous NaOH. The yellow precipitate was collected by filtration, washed with water and dried in vacuo over P2O5, then absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column. Elution with 2% ethyl acetate in dichloromethane afforded the title compound as a yellow solid (0.090 g, 26%); 1H-NMR (250 Mz, DMSO-d6) 7.39 (s, 2H, NH2), 8.39 (s, 1H, 6-H); LC-MS (ESI, m/z) 6.54 min—208, 210, 212 [(M+H)+, Cl2 isotopic pattern].
Reaction SMILES: C[CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[CH2:7]1OC1C.[OH-].[K+]>O1CCCC1.C(O)=O>[CH2:5]1[O:4][CH:6]1[CH3:2].[CH3:7][CH:3]1[CH2:2][CH2:6][CH2:5][O:4]1
Reactant: CC1CCOC1
Agent: CC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=CO
Product: CC1CCCO1
Yield: 3 %

Procedure:
195 parts of the catalyst used in Example 2 were introduced into a thermostatically regulated reaction vessel equipped with a stirring means. Then the reaction vessel was charged with a mixture of 900 parts tetrahydrofuran, 50 parts 3-methyl tetrahydrofuran and 40 parts formic acid. To this mixture, which was stirred constantly, 10 parts of propylene oxide per hour were then added at a uniform rate over a period of five hours. In this way, the propylene oxide concentration in the reaction mixture was kept constant at 0.08 wt. %. The reaction temperature was 50 C. After all the propylene oxide had been added, the reaction mixture was stirred for another four hours at reaction temperature. The resulting copolymer solution was separated from the catalyst by filtering. The filtrate was free of propylene oxide and consisted of 43% copolymer, 53% unreacted tetrahydrofuran and 4% 3-methyl tetrahydrofuran, as was determined by boildown under standard pressure and under vacuum. The solvent-free copolymer had a saponification number of 37 mg KOH/g and a hydroxyl number of 13 mg KOH/g. The product contained less than 0.3% cyclic oligomeric ethers. The ester-containing polymer was then mixed with an equal volume of methanol and, after addition of 10 parts of calcium hydroxide, was transesterified to glycol under standard pressure at 32° C. by distillation on a column with 20 theoretical trays, the methyl formate ester being distilled off. When the transesterification to glycol was complete, the calcium hydroxide used as transesterification catalyst was filtered off and the methanolic solution of the copolymer was boiled down completely—first under standard pressure and later under vacuum—using a film evaporater. The polymer obtained was pure, ester-free glycol and had a hydroxyl number of 51 mg KOH/g, which corresponds to a molecular weight of 2210. The 13C NMR spectrum showed that the copolymer had been formed from approximately 10% propylene oxide, 87% tetrahydrofuran and 3% methyl tetrahydrofuran. The product's dispersity Mw/Mn was 1.25. Its color index was below 5 APHA and the acid number less than 0.01 mg KOH/g.