Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([N:26]3[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]3)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)C3CC3)cc2[N+](=O)[O-])CC1
Yield: 98 %

Procedure:
Method 1 was followed using 4-chloro-3-nitrophenyl cyclopropyl ketone (1.0 eq), 1-Boc-piperazine (1.2 eq), and TEA (1.5 eq) at 55° C. for 48 hours yielding tert-butyl 4-(4-(cyclopropanecarbonyl)-2-nitrophenyl)piperazine-1-carboxylate (98%). LCMS (m/z): 376.1 (MH+); LC Rt=3.33 min.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[O:19][N:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]1[O:19][N:18]=[C:17]([CH2:16][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:29])=[O:2])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)[CH:21]=1
Reactant: COC(=O)COc1ccc(SCc2cc(-c3ccccc3Cl)on2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2cc(-c3ccccc3Cl)on2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 87A. mp 161-162° C.; IR (KBr) cm−1: 3177, 3065, 1706, 1475, 1432, 1233; 400 MHz 1H NMR (DMSO-d6): δ 13.00 (bs, 1H), 7.78-7.85 (m, 1H), 7.58-7.64 (m, 1H), 7.42-7.53 (m, 2H), 7.15 (d, 1H, J=8.6 Hz), 6.84 (s, 1H), 6.60 (d, 1H, J=8.6 Hz), 4.62 (s, 2H), 4.09 (s, 2H), 2.72-2.82 (m, 4H), 1.91 (pentet, 2H); MS m/z 416 (M+1). Anal. Calc'd for C21H18ClNO4S: C, 60.65; H, 4.36; N, 3.37. found: C, 60.56; H, 4.28; N, 3.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:15][C:14]3[C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11][CH2:10][CH2:9][C:8]=3[C:7]=2[CH:20]=1.C1OCCOCCOCCOCCOCCOC1.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:15][C:14]3[C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11][CH:10]=[CH:9][C:8]=3[C:7]=2[CH:20]=1
Reactant: COc1ccc2[nH]c3c(c2c1)CCSc1ccccc1-3
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c2c1)C=CSc1ccccc1-3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
9-Methoxy-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene (57 mg, 0.203 mmoL) in DMF (2 mL) was treated with KO2 (58 mg, 0.811 mmoL) and 18-Crown-6 (54 mg, 0.203) and the reaction mixture was stirred at room temperature for 6 hours. Water was added to quench the reaction. The mixture was then partitioned between EtOAc and saturated NH4Cl. The aqueous phase was extracted two times with EtOAc. The organic layer from each extraction was combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, 1:1 hexanes:EtOAc as eluent) to yield the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]2)[CH:27]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH:32]1[C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1cncc(C2CCCCN2)c1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2c2cccnc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(pyridin-3-yl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.99 minutes; C27H25Cl2N5O2 (522.43); mass spectrum: (M−H)−=521/523/525 (chlorine isotope).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Br.Br.[NH:13]1[CH:17]=[C:16]([CH2:18][CH2:19][S:20]C(=N)N)[N:15]=[CH:14]1.[OH-].[Na+]>C(O)C.O>[NH:13]1[CH:17]=[C:16]([CH2:18][CH2:19][S:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[N:15]=[CH:14]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N=C(N)SCCc1c[nH]cn1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(SCCc2c[nH]cn2)nc1

Procedure:
A hot solution of 0.2 g (1.3 mmol) of 2-chloro-5-nitropyridine in 5 ml of ethanol is added to a solution of 0.2 g (1.1 mmol) of S-{2-[1H-imidazol-4-yl]ethyl}isothiourea dihydrobromide in 2 ml of water. The resulting suspension is stirred under nitrogen. The reaction mixture is cooled to 0°-5° C. and a solution of 4 molar equivalents of sodium hydroxide (0.16 g) in 2 ml of water is added dropwise under N2. The reaction mixture is stirred for 1 h at the same temperature and for 3 h at 21° C. The reaction mixture is evaporated to dryness and the residue is subjected to column chromatography (silica gel) eluted with a gradient mixture of chloroform and methanol (1-10%) to provide the title compound which is then crystallized from 2-propanol, M.p.: 147°-148° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:19]1[CH:24]=[C:23]([CH:25]=[O:26])[C:22]([CH:27]=O)=[CH:21][CH:20]=1.CCOCC>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[CH2:27][C:22]3[C:23](=[CH:24][CH:19]=[CH:20][CH:21]=3)[C:25]2=[O:26])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: O=Cc1ccccc1C=O
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOc1cc(C(CS(C)(=O)=O)N2Cc3ccccc3C2=O)ccc1OC
Yield: 69.4 %

Procedure:
A stirred mixture 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (100 mg, 0.37 mmol) and 1,2-phthalic dicarboxaldehyde (49 mg, 0.37 mmol) in acetic acid (2 mL) was heated to reflux for 15 min. Removal of solvent in vacuo and chromatography gave an oil which was stirred with ether (2 mL). The resulting suspension was filtered to yield 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindolin-1-one as a light yellow solid (100 mg, 70% yield): mp, 130.0-134.0° C.; 1H NMR (CDCl3) δ 1.45 (t, J s=7 Hz, 3H, CH3), 2.96 (s, 3H, CH3), 3.70 (dd, J=4.5, 14.7, Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=6.9 Hz, 2H, CH2), 4.25 (d, J=16.5 Hz, 1 H, CHH), 4.31 (dd, J=10.3, 14.5 Hz, 1H, CHH), 4.46 (d, J=16 Hz, 1H, CHH), 5.71 (dd, J=4.5, 10.3 Hz, 1H, NCH), 6.84-7.01 (m, 3H, Ar), 7.38-7.56 (m, 3H, Ar), 7.85 (d, J=6.9 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.65, 41.33, 46.27, 52.33, 55.95, 56.00, 65.56, 111.45, 112.28, 119.30, 122.85, 123.85, 128.13, 129.89, 131.80, 132.27, 141.26, 148.88, 149.62, 169.09; Anal Calcd for C20H23NO5S: C, 61.68; H, 5.95; N, 3.60. Found: C, 61.68, H, 6.06; N, 3.62.
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>>[CH3:6][N:7]([CH:9]=[C:19]1[C:14](=[O:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18]1)[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 110 °C

Procedure:
To tert-butoxy bis(dimethylamino)methane (20.8 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (20.0 g) and the resulting mixture was heated at 110° C. for 16 h. After cooling to rt, the mixture was purified by flash chromatography on silica gel using a gradient elution of 5% methanol in methylene chloride to 10% methanol in methylene chloride. Concentration of the combined fractions containing the major product afforded the desired product a (11.8 g) as a dark orange oil which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]([S:5]([N:7]=[C:8]1[CH2:11][O:10][CH2:9]1)=[O:6])([CH3:4])[CH3:3].[F-].C[N+](C)(C)C.C[Si](C)(C)[C:20]([F:23])([F:22])[F:21]>C1COCC1>[CH3:4][C:2]([S:5]([NH:7][C:8]1([C:20]([F:23])([F:22])[F:21])[CH2:11][O:10][CH2:9]1)=[O:6])([CH3:1])[CH3:3]
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(C(F)(F)F)COC1
Temperature: -35 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
2-Methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (100 mg, 0.571 mmol) was dissolved in THF (2 mL). The solution was cooled down to −35° C. and added tetramethylammonium fluoride (63.8 mg, 0.685 mmol). The mixture was degassed and charged with argon. Trimethyl(trifluoromethyl)silane (0.134 ml, 0.856 mmol) in THF (1 mL) was added slowly via syringe. The reaction was stirred at this temperature for 2 h, warmed to −10° C. and quenched with saturated aqueous NH4Cl solution. The mixture was extracted with ethyl acetate, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to give the title compound (53 mg). LCMS m/z=246.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 1.29 (s, 9H), 3.79 (s, 1H), 4.78-4.85 (m, 3H), 4.98 (dd, J=7.6 and 1.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([N:8]2[C:17](=[O:18])[CH:11]3[CH2:12][CH:13](O)[CH2:14][CH2:15][N:10]3[C:9]2=[O:19])=[N:6][CH:7]=1.C(N(S(F)(F)[F:27])CC)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([N:8]2[C:17](=[O:18])[CH:11]3[CH2:12][CH:13]([F:27])[CH2:14][CH2:15][N:10]3[C:9]2=[O:19])=[N:6][CH:7]=1
Reactant: O=C1C2CC(O)CCN2C(=O)N1c1ncc(Cl)cc1F
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Product: O=C1C2CC(F)CCN2C(=O)N1c1ncc(Cl)cc1F
Reaction time: 1 h

Procedure:
2.6 g of 2-(5-Chloro-3-fluoro-pyridine-2-yl)-7-hydroxi-tetrahydroimidazo-(1.5-a)-pyridine-1,3-dione (isomer B) in 80 ml dichlorromethane is treated at −55° C.-−65° C. with 1.9 ml of diethylaminosulfur trifluoride (DAST) and stirred at the same temperature for 1 hr. The vessel is then allowed to stirr at room temperature over night. The resulting brownish solution is treated with ice and water and extracted with ethyl acetate. The extracts are washed with water, dried, filtered through a small siligcagel column and evaporated to give the desired product with m.p. 154-157° C.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].Br[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[CH3:19][N:20]1[C:24]([CH:25]=[O:26])=[CH:23][N:22]=[CH:21]1>C1COCC1>[CH3:19][N:20]1[C:24]([CH:25]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[OH:26])=[CH:23][N:22]=[CH:21]1
Reactant: Cn1cncc1C=O
Reactant: FC(F)(F)c1cc(Br)ccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccnc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of isopropylmagnesium chloride/lithium chloride complex (1.3 M in THF, 10.6 mL, 13.8 mmol) was added dropwise by syringe to a solution of 4-bromo-2-(trifluoromethyl)pyridine (3.12 g, 13.8 mmol) in dry THF (50 mL) at 0° C. After 30 min, a solution of 1-methyl-1H-imidazole-5-carbaldehyde in THF (1.38 g, 12.5 mmol) was added to the Grignard solution by syringe at 0° C. The reaction mixture was warmed to room temperature over 2 h after which it was quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate and washed with saturated aqueous NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-10% MeOH-DCM) to provide the title compound.
Reaction SMILES: [C:1]([N:9]1[CH2:17][C@@H:16]([OH:18])[CH2:15][C@H:10]1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([N:9]1[CH2:17][C@@H:16]([O:18][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:15][C@H:10]1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of (cis)-1-benzoyl-4-hydroxy-L-proline, methyl ester (1.9 g, 7.63 mmole) in pyridine (6 ml) was stirred under argon and treated with p-toluenesulfonyl chloride (1.75 g, 9.16 mmole). The reaction was stirred overnight, treated with additional p-toluenesulfonyl chloride (0.145 g, 0.76 mmole) and stirred for 24 hours. Ice water was added followed by ethyl acetate. The organic layer was washed with 1N HCl, brine, and dried. Filtration and concentration in vacuo afforded the title compound as a foam which was used without purification in the subsequent step.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1)(=O)=O.O[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:24]([C:23]1[CH:26]=[CH:27][C:20]([O:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:16])[O:17][CH3:18])=[CH:10][CH:9]=2)=[CH:21][CH:22]=1)=[O:25]
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Yield: 75.8 %

Procedure:
7 g (26 mmole) 4-[(methoxycarbonyl)amino]phenethyl methanesulfonate, 6.2 g (51 mmole) 4-hydroxybenzaldehyde and 7.05 g potassium carbonate in acetonitrile was refluxed for 3 h. The solvent was evaporated in vacuo, 1 M sodium hydroxide was added and the product was extracted with dichloromethane, washed with brine, dried and the solvent was evaporated. The reaction was not completed and therfore restarted with 3.1 g 4-hydroxybenzaldehyde and 3.5 g potassium carbonate in acetonitrile and refluxed for 4 h. The solvent was evaporated and the residue was stirrred in dichloromethane over night. The precipitate was filtered off and the solvent was evaporated to give 5.9 g (yield 75.8%) of methyl N-{4-[2-(4-formylphenoxy)ethyl]phenyl}carbamate wich was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:7]=1[CH2:8][O:9][C:10]1[C:11]2[N:12]([C:16](CC#C)=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:4].C=O.CNC>O1CCOCC1.O>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:7]=1[CH2:8][O:9][C:10]1[C:11]2[N:12]([CH:16]=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(=O)OC)cccn12
Agent: C=O
Agent: CNC
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)Nc1cccc(C)c1COc1cccn2cc(C)nc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
To a solution of 8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (230 mg) in 1.4-dioxane (4.6 ml) were added 36% formaldehyde (105 mg), 50% dimethylamine in water (142 mg) and cuprous chloride (12.5 mg). After the mixture was stirred at 50° C. for 5 hours, 1.4-dioxane was evaporated under reduced pressure. The resultant residue was dissolved in chloroform (20 ml) and insoluble material was filtered off. The filtrate was washed with an aqueous solution of sodium bicarbonate and water in turn, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 3-(4-N,N-dimethylamino-2-butynyl(-8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methylimidazo-[1,2-a]pyridine (175 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[F:12][C:13]1[C:18](O)=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1[F:23].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.O1CCCC1>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C:18]2[C:17]([F:20])=[C:16]([F:21])[C:15]([F:22])=[C:14]([F:23])[C:13]=2[F:12])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C=Cc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
In a mixture solvent of 500 mL of ethyl acetate and 150 mL of tetrahydrofuran were dissolved 50 g of 4-vinylbenzoic acid and 62.1 g of pentafluorophenol, and the solution was ice-cooled. To the solution was added 69.65 g of dicyclohexylcarbodiimide, and the mixture was stirred under ice-cooling for 1 hour and then at room temperature for 1 hour. Precipitated dicyclohexylurea was filtered off and the filtrate was concentrated under a reduced pressure. To the residue was added 150 mL of hexane, and precipitated dicyclohexylurea was filtered off. Then, the filtrate was concentrated under a reduced pressure to give 99 g of pentafluorophenyl 4-vinylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH3:15])=[O:5].FC(F)(F)S(O)(=O)=O.[CH3:29][C:30]([CH3:32])=[CH2:31].[OH-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([O:12][C:30]([CH3:32])([CH3:31])[CH3:29])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH3:15])=[O:5]
Reactant: C=C(C)C
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OC(C)(C)C
Yield: 19.9 %

Procedure:
A solution of 2,6-dichloro-5'-hydroxy-4'-methoxy-2'-methyl-benzophenone (3.0 g; 9.6 mmol) in 50 ml of methylenechloride is cooled down to -70° C., trifluoromethanesulfonic acid (0.3 ml) is added, then a stream of 2-methylpropene (5.5 g; 100 mmol) is introduced within 4 hours. Triethylamine (1.2 ml) is added, the temperature goes up to 20° C. The solution is shaken twice with diluted sodium hydroxide and the solventis evaporated. The residue is purified chromatographically (flash column with 30 g of silicagel, elution with toluene/acetone 20:1 (v/v)). The residue is treated with petrolether to give 0.7 g of white crystals (20% y); mp. 102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:14]([Si:17]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])Cl)([CH3:16])[CH3:15]>ClCCl>[CH3:15][CH:14]([Si:17]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH3:16]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Nc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)[Si](Oc1ccc(N)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 4-aminophenol (20 g, 183 mmol) in dichloromethane (300 ml) was added 1H-imidazole (16.2 g, 240 mmol, 1.3 eq.). Triisopropyl chlorosilane (53.1 g, 275 mmol, 1.5 eq.) was added dropwise with stirring for 2 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 25% ethyl acetate in petroleum ether to afford 4-[[tris(propan-2-yl)silyl]oxy]aniline as brown oil (34 g, 70%); (ES, m/z): [M+H]+ 266; 1H NMR (300 MHz, CDCl3): δ 6.66-6.72 (m, 2H), 6.55-6.59 (m, 2H), 3.23 (s, 2H), 1.20-1.30 (m, 3H), 1.13 (s, 18H).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](O)=[O:4].CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.[NH2:28][C:29]1[N:34]2[N:35]=[CH:36][C:37]([C:38]3[CH:39]=[N:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:42][CH:43]=3)=[C:33]2[N:32]=[C:31]([CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[C:30]=1[C:56](=[O:59])[CH2:57][OH:58].C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:28][C:29]1[N:34]2[N:35]=[CH:36][C:37]([C:38]3[CH:39]=[N:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:42][CH:43]=3)=[C:33]2[N:32]=[C:31]([CH:50]2[CH2:55][CH2:54][N:53]([C:3](=[O:4])[C@H:2]([OH:1])[CH3:6])[CH2:52][CH2:51]2)[C:30]=1[C:56](=[O:59])[CH2:57][OH:58]
Reactant: C[C@@H](O)C(=O)O
Reactant: Nc1c(C(=O)CO)c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)C(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c2C(=O)CO)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (R)-2-hydroxypropanoic acid (13.8 mg, 0.16 mmol), EDCI (46 mg, 0.24 mmol), and 1-hydroxybenzotriazole (16.22 mg, 0.12 mmol) in DMF (2 ml) was stirred at room temperature for 10 min. To this 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyethanone (58.77 mg, 0.12 mmol) was added followed by N,N-diisopropylethylamine (0.1 ml, 0.6 mmol). It was stirred further for 20 min at room temperature at which time LC/MS analysis confirmed full consumption of starting material. This crude compound was submitted to the analytical group for purification to afford the desired (R)-1-(4-(7-amino-6-(2-hydroxyacetyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)-2-hydroxypropan-1-one. LCMS: 3.27 mins, m/z=501.0 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[F:9][C:10]([F:14])([F:13])[CH2:11][NH2:12]>C(OCC)(=O)C>[F:9][C:10]([F:14])([F:13])[CH2:11][NH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccccn1
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: FC(F)(F)CNc1ccccn1
Temperature: 220 °C
Yield: 468.5 %

Procedure:
A mixture of 2-fluoropyridine (2.00 g, 20.6 mmol) and 2,2,2-trifluoroethylamine hydrogen chloride (5.00 g, 36.9 mmol) was heated to 220° C. for 30 min in a microwave reactor. The same reaction was repeated 5 times. The reaction mixtures from all 6 reactions were cooled, combined and diluted with ethyl acetate (150 mL). The organic mixture was neutralized by washing with saturated aqueous sodium bicarbonate, water (30 mL) and brine (30 mL). The organic phase was dried over Na2SO4 and concentrated, and the resulting residue was purified by chromatography on silica gel using 80% ethyl acetate/hexane as eluant to give the title compound as a white solid (17.0 g).
Reaction SMILES: [NH2:1][C:2]1[C:13]([F:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[NH2:1][C:2]1[C:13]([F:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:3]=1[C:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: CON(C)C(=O)c1cc(Cl)cc(F)c1N
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: Nc1c(F)cc(Cl)cc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 70.7 %

Procedure:
To a solution of 2-amino-5-chloro-3-fluoro-N-methoxy-N-methyl-benzamide (250 mg, 1.07 mmol) in diethyl ether (5 ml) was added phenylmagnesium bromide (2.69 ml, 1M in THF, 2.69 mmol) dropwise at 0° C. The resulting mixture was stirred for 2.5 h at 0° C. and the quenched by addition of saturated NH4Cl solution. The mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 98:2-95:5) to afford the title compound (189 mg, 70%) as yellow solid. MS (ESI): 250.2 (M+H)+.