Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3](O)[CH:2]=1.[OH-:15].[K+].Br[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[Br:20]>CS(C)=O>[Br:20][C:19]([F:22])([F:21])[C:18]([F:24])([F:23])[O:15][C:10]1([O:13][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[Br:20])[CH:11]=[CH:12][C:7]([C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=2)=[CH:8][CH2:9]1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: [OH-]
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [K+]
Solvent: CS(C)=O
Product: FC(F)(Br)C(F)(F)OC1(OC(F)(F)C(F)(F)Br)C=CC(c2ccccc2)=CC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 91.3 %

Procedure:
A solution of 28.7 g (0.15 mol) of 4,4′-bisphenol in 75 mL of DMSO was placed into a 500 mL round-bottom flask. The solution was purged with nitrogen gas at room temperature (23° C.) for 2-3 hours. Then, 140.85 mL of 2.13M (0.300 mol) of standardized aq KOH was added dropwise to the solution in the flask, while the flask rested in an ice-bath and the nitrogen gas purge continued. After the KOH solution was added, the reaction mixture was heated to 100° C. and stirred for 1 day, followed by distilling off most of the water. The remaining solvent was evaporated off slowly under reduced pressure (10 torr). The reaction product was then dried thoroughly at 140-150° C. with fill vacuum (10−2 torr) for at least 2 days. Then, a solution of 104 g (0.4 mol) of 1,2-dibromotetrafluoroethane in 100 mL of well-dried DMSO was transferred to the flask via a closed system. The mixture was stirred at 35-40° C. for 4 days, followed by filtration to remove the solid precipitate. The precipitate was washed with acetone three times. The combined acetone solution was then washed in a separatory fimnel, first with a 5% sodium bicarbonate water solution, then with 0.1N HCl, and finally washed with distilled water and dried over sodium sulfate overnight. After removing solid material by filtration and evaporating the solvents at reduced pressure (10 torr), the crude product was purified by sublimation with an oil bath at a temperature around 100-110° C. A product of 75 g (0.137 mol) of 4,4-di(2-bromotetrafluoroethoxy)biphenyl was obtained at a yield of 91%. The amount of hydrogen by-product in the fmal product was around 1%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH3:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[F:23])=[O:4].[OH-].[Na+]>CO.O1CCCC1>[F:23][C:6]1[CH:7]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH3:18])=[CH:15][CH:16]=2)[CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccc(N(C)S(C)(=O)=O)cc2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Procedure UU: To a stirring solution of 3-Fluoro-4′-(methanesulfonyl-methyl-amino)-biphenyl-4-carboxylic acid methyl ester (see Intermediate Preparation 33) (11.0 mmol) in 1:1 methanol/tetrahydrofuran, add 2N sodium hydroxide (3.0 mmol) and stir at room temperature for 4 hours. After this time wash the reaction with 1N hydrochloric acid while extracting with dichloromethane. Dry the organics with sodium sulfate, decant, and concentrate in vacuo. MS (m/e): 322.1 (M−1)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:26]([N:33]1[CH:37]=[CH:36]N=C1)(N1C=CN=C1)=[O:27].[CH:38]1([CH2:41]CCN)[CH2:40][CH2:39]1>ClCCl>[CH:38]1([CH2:41][CH2:36][CH2:37][NH:33][C:26]([NH:1][C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]3)=[CH:4][CH:3]=2)=[O:27])[CH2:40][CH2:39]1
Reactant: NCCCC1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Solvent: ClCCl
Product: O=C(NCCCC1CC1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.5 %

Procedure:
[4-(6-Aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone (200 mg, 0.57 mmol) was slowly added to an ice cold solution of 1,1′-carbonyldiimidazole (110 mg, 0.683 mmol) in anhydrous dichloromethane (15 mL). The temperature was then raised to ambient temperature and the reaction mixture was stirred for another 4 hours. 3-Cyclopropylpropylamine (48.5 mg, 0.569 mmol) was then added to the reaction mixture which was stirred at ambient temperature overnight under nitrogen. The reaction mixture was washed by saturated sodium bicarbonate and brine solution, concentrated and purified by flash column chromatography to yield the product as a white solid (23 mg, 8.5% yield). 1H NMR (300 MHz, CDCl3) δ 10.2, 7.68-7.83, 7.72, 7.65, 7.63, 7.55, 7.36, 7.04, 3.95-4.02, 3.83-3.95, 3.50-3.68, 3.40-3.50, 3.26-3.38, 1.60-1.72, 1.17-1.30, 0.71-0.80, 0.44-0.50, −0.06-0.013. MS (ES+) m/z 477 (M+1).
Reaction SMILES: [O:1]([CH2:19][CH:20]([CH3:29])[CH2:21][CH2:22][CH2:23][C:24](C)(O)[CH:25]=C)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:30]([O:36]CC)(=O)[CH2:31][C:32]([CH3:34])=O.[C:39]([O-])(=O)C.[Na+]>>[O:1]([CH2:19][CH:20]([CH3:29])[CH2:21][CH2:22][CH2:23]/[C:24](/[CH3:25])=[CH:34]\[CH2:32][CH2:31][C:30](=[O:36])[CH3:39])[Si:2]([C:15]([CH3:16])([CH3:17])[CH3:18])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC(C)(O)CCCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: [Na+]
Product: CC(=O)CC/C=C(/C)CCCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 205 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
8-t-Butyldiphenylsiloxy-3,7-dimethyl-1-octen-3-ol (60.33 g) is treated with ethyl acetoacetate (28.8 ml) and anhydrous sodium acetate (232 mg) and the mixture is allowed to stir for 2 hours at 205° C. under a short path distillation head to remove the ethanol formed in the reaction. The crude reaction mixture is purified via silica gel chromatography using ethyl acetate-hexane gradients to give 6 E/Z-1-t-butyldiphenylsiloxy-2,6-dimethyl-10-oxo-undec-6 -ene (32.9 g, 50%) as a yellow oil: ir (neat) 5.8μ (C=O); nmr (CDCl3)δ0.9 (d, CH3CH<), 1.05 [s, (CH3)3C], ##STR7## 2.08 ##STR8## 3.48 (d, 2H, OCH2CH<), 5.03 (b, 1H, C=CH--), 7.17-7.8 (m, 10 H, 2φ); m.s., M+ 450 (parent peak) not observed but M-57 (t-Bu) 393 present. A mixture of 60/40 E/Z isomers is observed by gas chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C=O)C>[CH2:27]([O:14][C:12]1[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[N:13]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(F)(F)F)nc(-c2ccc(N)cn2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound of example 15 (0.200 g, 0.78 mmol) in DMF (3 mL), was added K2CO3 (0.162 g, 1.170 mmol) and the mixture was stirred at 25° C. for 10 minutes, followed by slow addition of allyl bromide (0.14 g, 1.17 mmol). The reaction mixture was stirred at 25° C. for 45 minutes. DMF was removed under vacuum, and the reaction mass quenched by water, extracted with ethyl acetate (3×20 mL), dried over sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 5% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[N:3]=1
Reactant: O=[N+]([O-])c1cccc(Br)n1
Reactant: OB(O)c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(-c2c(F)cccc2F)n1
Temperature: 120 °C

Procedure:
To a solution of 2-bromo-6-nitropyridine [21203-78-1] (200 mg, 0.99 mmol) and 2,6-difluorophenylboronic acid [162101-25-9] (311 mg, 1.97 mmol) in dioxane (4 mL) and water (1 mL) was added potassium carbonate (340 mg, 2.46 mmol) and Pd(PPh3)4 (114 mg, 0.099 mmol). The solution was heated for 60 min at 120° C. under microwave irradiation. More 2,6-difluorophenylboronic acid (622 mg, 3.94 mmol) was added to the mixture followed by heating at 120° C. for 120 min under microwave irradiation. The reaction mixture was then diluted with EtOAc and the resulting solution was washed successively with saturated aqueous NaHCO3 solution and brine, the organics were then dried (Phase separator) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 9:1) to give the title compound. MS (LC-MS): 237 [M+H]+, 259 [M+Na]+; tR (HPLC conditions k): 3.44 min.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:5][CH:6]=1.[CH3:15][NH:16][CH3:17].O1CCOCC1.Cl[S:25](O)(=[O:27])=[O:26]>>[NH2:13][C:11]1[N:10]=[C:9]([NH2:14])[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[C:6]([S:25](=[O:27])(=[O:26])[N:16]([CH3:17])[CH3:15])[CH:5]=2)[N:12]=1
Reactant: O=S(=O)(O)Cl
Reactant: Nc1nc(N)nc(-c2ccccc2)n1
Reactant: CNC
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)c1cccc(-c2nc(N)nc(N)n2)c1
Reaction time: 1 h

Procedure:
5.7 g of benzoguanamine is heated in 12 g of chlorosulfonic acid at 130° to 140° C. for 4 hours. After cooling, the reaction mixture is added dropwise into a mixture of 40 ml of 40% aqueous dimethylamine and 50 ml of dioxane under agitation and ice cooling, and after one hour agitation, the mixture is evaporated to dryness under vacuum. Thereafter, water is added to the mixture and the separated crystals are filtered out and recrystallized from dioxane. Melting point: 250°-251° C.; yield: 8.8 g.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([F:15])[CH:8]=[C:7]([F:16])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:19])=O>>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([F:15])[CH:8]=[C:7]([F:16])[C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=C(O)c1c(F)cc(F)c(C(F)(F)F)c1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c(F)cc(F)c(C(F)(F)F)c1F
Temperature: 50 °C

Procedure:
5.8 g (0,024 mol) of 2,4,6-trifluoro-3-trifluoromethylbenzoic acid are added in portions at room temperature to 40 ml of thionyl chloride. After metering has ended, the mixture is heated at 50° C. until the evolution of gas has ceased. The excess thionyl chloride is then removed by distillation, and the crude product is reacted further directly.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[CH3:20][C:21]1(C)[C:25](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCOCC1>[CH3:20][CH:21]([C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])[CH3:25]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccnnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nnccc1CN1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
2-[(3-Chloropyridazin-4-yl)methyl]-1H-isoindole-1,3(2H)-dione (137 mg, 0.5 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (252 mg, 0.28 mL, 1.5 mmol), tetrakis(triphenylphosphine)palladium (57.8 mg, 0.05 mmol) and sodium carbonate (106 mg, 2.00 mmol) were mixed with water (0.2 mL) and 1,4-dioxane (0.9 mL) and stirred at 110° C. for 8 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. The resulting residue was mixed with 4 M hydrogen chloride/1,4-dioxane (5 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2). The obtained colorless solid (76 mg) and 10% palladium-carbon (50 wt %, 100 mg) were stirred in methanol (5 mL) under hydrogen atmosphere (1 atm) at room temperature for 16 hours. After filtering through celite, the filtrate was evaporated under reduce pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the desired product (76.3 mg, 54% yield).
Reaction SMILES: C(O[C:9](=O)[NH:10][CH2:11][CH2:12][NH:13][C:14]1[C:19]([C:20]#[N:21])=[C:18]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[N:17]=[C:16]([NH2:27])[N:15]=1)C1C=CC=CC=1.[C:29]1(=O)[CH2:34][CH2:33]C[CH2:31][CH2:30]1.[H][H]>O1CCOCC1.C(O)C.[Pd]>[NH2:27][C:16]1[N:15]=[C:14]([NH:13][CH2:12][CH2:11][NH:10][CH:9]2[CH2:33][CH2:34][CH2:29][CH2:30][CH2:31]2)[C:19]([C:20]#[N:21])=[C:18]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[N:17]=1
Reactant: O=C1CCCCC1
Reactant: [H][H]
Reactant: N#Cc1c(NCCNC(=O)OCc2ccccc2)nc(N)nc1-c1ccco1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: N#Cc1c(NCCNC2CCCCC2)nc(N)nc1-c1ccco1
Yield: 46.2 %

Procedure:
A solution of 200 mg (0.53 mmol) [2-(2-amino-5-cyano-6-furan-2-yl-pyrimidin-4-ylamino)-ethyl]-carbamic acid benzyl ester and 0.055 ml (0.53 mmol) cyclohexanone in 10 ml dioxane and 5 ml ethanol was stirred with a spatula end of 10% palladium on charcoal under 1 atm of hydrogen for 4 h at room temperature. After filtration to remove the catalyst, the reaction mixture was concentrated in vacuo and the residue triturated in ether to afford 80 mg (46%) 2-amino-4-(2-cyclohexylamino-ethylamino)-6-furan-2-yl-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 327 (M+H+, 100), 228 ([M+H—C6H11NH2]+, 40).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.BrC1C=CC2[NH:30]C(=O)OC(=O)C=2C=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:18][C:17]2[NH:30][CH2:19][CH2:20][N:16]=2)=[C:3]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:4]=1
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: C1CCNC1
Reactant: Nc1ccc(Br)cc1C(=O)N1CCCC1
Product: O=C(c1cc(Br)ccc1NCC1=NCCN1)N1CCCC1

Procedure:
{2-amino-5-bromophenyl}(1-pyrrolidinyl)methanone (prepared from pyrrolidine and 6-bromo-2H-3,1-benzoxazine-2,4(1H)-dione using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give {5-bromo-2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]phenyl}(1-pyrrolidinyl)methanone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[O:24]1[CH2:27][CH:26](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25]1>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:26]3[CH2:27][O:24][CH2:25]3)=[CH:23][C:6]1=2
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Product: CC1(C)c2cc(OC3COC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and toluene-4-sulfonic acid oxetan-3-yl ester.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[CH2:10][CH:11]([NH2:13])C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:17]=CC(S(O)(=O)=O)=C[CH:21]=1.C(N(CC)CC)C.C(Cl)(=[O:36])C=C>CCOCC>[CH2:1]([O:8][C:9]([C:10](=[CH:15][CH:16]([CH3:17])[CH3:21])[C:11]([NH2:13])=[O:36])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(N)CC(=O)OCc1ccccc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C=C(C(N)=O)C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
Next, 50 g of β-aminobutyric acid benzyl ester·p-toluenesulfonate were dispersed in 300 ml of ether containing 54.3 ml of triethylamine. To this dispersion were slowly added 12.7 ml of acryloyl chloride at 0° C. and stirred for 2 hours. The ether layer was recovered, condensed and purified by silica gel chromatography to obtain 19.59 g of the desired 2-(benzyloxycarbonyl)isopropyl acrylamide as a white crystal. The synthesis was confirmed by 1H-NMR spectrometry and elementary analysis. The results of the 1H-NMR spectrometry and the elementary analysis are set forth below. The underlined portion shows the position of the corresponding proton in the compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C1CCCCC1>N1C=CC=CC=1>[C:20]([O:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1ccc(-c2nc3c(O)cccc3s2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCCCC1
Product: CC(=O)Oc1cccc2sc(-c3ccc(C(=O)O)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
The 4-(4-hydroxybenzothiazol-2-yl)benzoic acid (6.9 g) obtained in Example 3 was dissolved in 15 ml of pyridine, and 2.6 g of acetic anhydride was added dropwise. The mixture was stirred at room temperature for 2 hours, and 160 ml of cyclohexane was added. The precipitated crystals were collected by filtration, washed with cyclohexane and then diethyl ether, and recrystallized from acetonitrile to give 4.0 g of 4-(4-acetoxybenzothiazol-2-yl)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.S(Cl)([Cl:35])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][Cl:35])=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCc1ccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3[nH]2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Fc1ccc(Nc2ncnc3[nH]c(-c4ccc(CCl)cc4)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
184 mg (0.5 mmol) {4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol are suspended in 15 ml toluene. Pyridine (44 μl, 0.55 mmol) and thionyl chloride (40 μl, 0.55 mmol) are added and the mixture is stirred at RT for 16 h. A second portion of the same amounts of pyridine and thionyl chloride are then added and the mixture stirred for 1 additional hour. The solvent is evaporated and the residue suspended in water containing a small amount of sodium bicarbonate (pH˜8). After filtration, the product was thoroughly washed with water and ether and dried to give crude title compound; m.p.>300° C.; Rf (dichloromethane/ethanol 95:5 plus 1% conc. ammonia)=0.42; HPLC tR=11.33 min.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:10]1(C(O)=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(C1C=CC(C#N)=C(Cl)N=1)(C)(C)C>>[Cl:1][C:2]1[N:9]=[C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C(O)C1CCCC1
Reactant: N#Cc1cccnc1Cl
Agent: CC(C)(C)c1ccc(C#N)c(Cl)n1
Product: N#Cc1ccc(C2CCCC2)nc1Cl
Yield: 41 %

Procedure:
This compound was synthesized in 41% yield from 2-chloronicotinonitrile and cyclopentanecarboxylic acid using the same procedure as for 6-tert-butyl-2-chloronicotinonitrile.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.F[C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[N:26][CH:27]=1.O>CC(N(C)C)=O>[C:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][CH:8]([O:7][C:22]2[CH:27]=[N:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])nc2)CC1
Reaction time: 1 h
Yield: 49.7 %

Procedure:
Add potassium tert-butoxide (4.84 g) to a solution of tert-butyl 4-hydroxy-1-piperidine-carboxylate (8.76 g) in dimethylacetamide (DMA, 39 mL) at 0° C. under nitrogen. Stir for 1 h and add drop wise a solution 5-fluoro-2-nitro-pyridine (5 g) in DMA (78 mL). Let the reaction stir at RT overnight. Add water and stand for 1 h. Filter, wash with water. Purify by silica gel column chromatography eluting with DCM/EA (0-15%) to afford 5.65 g of the title compound. MS (ES+): m/z=324 (M+H)+.