Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2n[nH]c3ccccc23)cc1
Temperature: 100 °C
Yield: 5.4 %

Procedure:
A mixture of 3-bromo-1H-indazole (0.20 g, 1.0 mmol), 4-methoxyphenylboronic acid (0.228 g, 1.5 mmol), and tetrakis(triphenylplhosphine)palladium(0) (0.228 g, 0.1 mmol) in ethylene glycol dimethyl ether (5 mL) and 2.0 M sodium carbonate solution (6 mL) under nitrogen was heated at 100° C. for 18 hours. It was quenched by water and extracted with chloroform. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15–30% ethyl acetate/hexane) to provide the title compound (0.012 g, 5% yield): 1N NMR (CDCl3) δ 10.4 (br s, 1H), 8.01 (d, 1H), 7.92 (d, 2H), 7.46 (m, 2H), 7.22 (m, 1H), 7.06 (d, 2H), 3.89 (s, 3H); EI-MS (m/z) 224 [M]+.
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:29]1([CH2:35][CH2:36][CH2:37][C:38](Cl)=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCC.O1CCCC1>[C:29]1([CH2:35][CH2:36][CH2:37][C:38]([O:6][CH:7]([C:20]2[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OC(=O)CCCc1ccccc1)c1coc([Si](C)(C)C)c1
Reaction time: 0.17 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.47 ml, 0.79 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (256.4 mg, 0.76 mmol), prepared as in Example 38, in tetrahydrofuran (5 ml) at -78 degrees under argon. After 10 minutes, a solution of 4-phenylbutyryl chloride (145 mg, 0.79 mmol) was added. Stirring was continued at room temperature for 2 days and the mixture was quenched with water. Extraction and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative thin-layer chromatography (20×20 cm, 1000 micron silica plate; developed with 10% ethyl ether/hexane) The title ester was obtained as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1.F[C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[C:25]=1[C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:24]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH2:33][CH2:34][C:35]5[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=5)[C:25]=4[C:26]#[N:27])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N#Cc1c(F)cccc1NCCc1ccncc1
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)cn2C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(NCCc2ccncc2)cccc1Oc1ccc(-c2cn(C3CCOC3)c3ncnc(N)c23)cc1
Temperature: 120 °C

Procedure:
A mixture of 4-[4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-phenol (0.517 g), 2-fluoro-6-(2-(4-pyridinyl)ethylamino)benzonitrile (0.42 g), potassium carbonate (0.48 g) and dimethylformamide (20 ml) were heated at 120° C. under nitrogen for 8 hours. The mixture was allowed to cool, diluted with water then extracted with ethyl acetate to give a solid which was recrystallised from ethyl acetate to give solid which was purified by flash column chromatography on silica using ethyl acetate and then ethyl acetate/methanol (9:1, 8:1, 4:1) to give 2-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]-6-(2-(4-pyridyl)ethylamino)-benzonitrile, m.p 212-213° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:45])[N:14]([CH2:18][C:19]([NH:21][CH:22]([C:31](=[O:44])[CH2:32][O:33][C:34](=[O:43])[C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:45])[N:14]([CH2:18][C:19]([NH:21][CH:22]([C:31](=[O:44])[CH2:32][O:33][C:34](=[O:43])[C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O)C(=O)COC(=O)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(NC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O)C(=O)COC(=O)c1c(Cl)cccc1Cl
Temperature: 20 °C
Yield: 75.3 %

Procedure:
The ester 56a (210 mg, 0.356 mmol) in dichloromethane (0.5 ml) was cooled to 0° C. and treated with trifluoroacetic acid (0.5 ml), stirred and warmed to 20° C. over 30 minutes. The solution was evaporated to dryness under reduced pressure, redissolved in dichloromethane and concentrated (×3). The residue was triturated with ethyl acetate and diluted with ether to afford the title compound 162 mg (85%) as a colorless solid: m.p. 165-8° C. (decomposition); [α]D23 −38.8° (c 0.1, CH3OH); IR (KBr) 3332, 3275, 1723, 1658, 1649, 1597, 1581, 1562, 1526, 1432, 1385, 1258, 1218, 1206; 1H NMR (d6-DMSO) δ8.96 (1H, d, J=7.3), 8.34 (1H, s), 7,85 (1H, dd, J=7.3), 7,58 (3H, m), 7.35 (5H, m), 6.29 (1H, t, J=7.3), 5,26 (2H, m), 5.15 (2H, s), 4.69 (3H, m), 2.75 (2H, m). Anal. Calcd. C27H23N3O9Cl2: C, 53.66; H, 3.84; N, 6.95. Found: C, 53.36; H, 3.90; N, 6.81. M.S. (+FAB); 604 (M++1), 285, 241, 195, 173, 149, 91.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=CC=1.[C:32](=O)([O:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1)[O:33]C1C=CC([N+]([O-])=O)=CC=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[O:43][CH2:44][C:45]4[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=4)=[C:3]([O:24][CH3:25])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(OCc1cccnc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1cccnc1
Temperature: 100 °C
Yield: 33.8 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (25 mg, 0.074 mmol) was dissolved in dichloromethane (0.7 mL). Pyridine (0.7 mL) was added followed by 4-nitrophenyl (3-pyridylmethyl) carbonate (30 mg, 0.110 mmol). After heating at 100° C. overnight, the solvent was removed and the residue was purified by preparative LC/MS to give 3-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (12 mg, 0.025 mmol). 1H NMR (CDCl3-d) δ 2.08 (m, 4H), 3.65 (m, 2H), 3.92 (s, 3H), 4.15 (m, 2H), 4.96 (m, 1H), 5.26 (s, 2H), 5.54 (bs, 2H), 6.97 (s, 1H), 7.04 (s, 1H), 7.08 (d, J=8.2 Hz, 1H), 7.35 (m, 2H), 7.79 (d, J=7.8 Hz, 1H), 8.15 (m, 1H), 8.29 (s, 1H), 8.61 (s, 1H), 8.71 (s, 1H). LC/MS MH+=475.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[Si:14]([O:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC1CCNCC1
Reaction time: 22 h
Yield: 85.9 %

Procedure:
2-(piperidin-4-yl)ethanol (2.00 g, 15.5 mmol), t-butylchlorodimethylsilane (2.57 g, 17.0 mmol), and imidazole (1.05 g, 15.5 mmol) were taken up in dichloromethane (15 mL) and stirred for 22 hours. This solution was added to aqueous K2CO3 (80 mL) and extracted with dichloromethane (3×30 mL). The combined organics were dried (MgSO4) and evaporated to give a pale yellow oil. Silica gel chromatography (gradient elution dichloromethane+2.5% TEA/0-10% methanol) afforded a white solid. This solid was added to aqueous K2CO3 (60 mL) and extracted with dichloromethane+10% methanol (3×30 mL), the organics dried (MgSO4) and evaporated to give compound 292 as a yellow oil (3.24 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][C:14]([OH:18])([C:16]#[CH:17])[CH3:15].C(NC(C)C)(C)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]#[C:16][C:14]([OH:18])([CH3:15])[CH3:13])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: Nc1ccc(Br)cc1S(N)(=O)=O
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(O)C#Cc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 100 °C
Yield: 45.4 %

Procedure:
2-Amino-5-bromobenzenesulfonamide (2 g, 7.96 mmol), copper(I) iodide (0.076 g, 0.40 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.280 g, 0.40 mmol) were slurried in anhydrous N,N-dimethylformamide (6 mL) in a microwave vial. 2-Methyl-3-butyn-2-ol (2.316 mL, 23.89 mmol) followed by diisopropylamine (3.37 mL, 23.89 mmol) were added, the vial was capped, purged with argon and the mixture was heated in a microwave at 100° C. for 30 min. The mixture was filtered and the solvent was evaporated in vacuo. Purification by column chromatography, using a gradient of 60-70% ethyl acetate in heptane as the eluent, gave 0.92 g (46% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:20]([CH3:25])=[N:21][NH:22][C:23]=2[CH3:24])=[CH:8][CH:7]=1.[H-].[K+].Br[CH2:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>O1CCCC1.CS(C)=O>[CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:20]([CH3:25])=[N:21][N:22]([CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:23]=2[CH3:24])=[CH:10][CH:11]=1
Reactant: COC(=O)/C=C/c1ccc([C@@H]2CCCN2CCc2c(C)n[nH]c2C)cc1
Reactant: BrCC1CCOCC1
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc([C@@H]2CCCN2CCc2c(C)nn(CC3CCOCC3)c2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.6 %

Procedure:
To an ice cold mixture of (E)-3-(4-{(S)-1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester (0.85 g, 2.4 mmol) and potassium hydride (115 mg, 2.88 mmol) in 4.0 mL tetrahydrofuran:dimethyl sulfoxide (9:1 v/v) was added 4-bromomethyltetrahydropyran (945 mg, 5.28 mmol). The mixture was slowly warmed to room temperature and stirred under nitrogen for 16 h. It was then quenched with aqueous ammonium chloride and added with ethyl acetate. The layers were separated and the organic layer was washed with more aqueous ammonium chloride. The aqueous layers were then washed with more ethyl acetate and the combined organic extracts were dried over magnesium sulfate and concentrated to a yellow oil. The oil was then purified via silica gel column chromatography (100:0 to 0:100 heptane:ethyl acetate) to give (E)-3-[4-((S)-1-{2-[3,5-dimethyl-1-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-4-yl]-ethyl}-pyrrolidin-2-yl)-phenyl]-acrylic acid methyl ester (160 mg, 0.35 mmol, 14% yield) as a yellow oil. LC/MS (m/z): 452.5 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[C:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH2:18](O)[CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26].C(O)C(O)CCl.C(=O)([O-])[O-].[Na+].[Na+]>CC(CC(C)C)=O>[CH3:1][C:2]1([CH3:17])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[C:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[CH2:13][CH2:12]1
Reactant: CC1(C)Cc2ccccc2C1=C1CCNCC1
Reactant: OCCOCCOCCO
Agent: O=C([O-])[O-]
Agent: OCC(O)CCl
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC1(C)Cc2ccccc2C1=C1CCN(CCOCCOCCO)CC1
Reaction time: 12 h

Procedure:
2.5 g 4-(2,2-dimethyl-indane-1-ylidene)-piperidine, 1.95 g triethyleneglycol-monochlorhydrin and 2 g sodium carbonate in 50 ml methylisobutylketone are refluxed with stirring for 12 hours. After cooling, the reaction mixture is filtered and the filtrate evaporated. The residue is dissolved in ether, the solution washed two times with a little cold water, dried over sodium sulfate, filtered and evaporated, to give the title compound as a viscous oil. The neutral oxalate melts at 82°-85°.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][N:18](C([O-])=O)[CH2:17][CH2:16][N:15]3C([O-])=O)=[CH:10][CH:9]=2)[N:4]=1>C(OCC)(=O)C.CO>[ClH:1].[ClH:1].[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][NH:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)[N:4]=1
Reactant: Cc1nc(-c2ccc([C@H]3CN(C(=O)[O-])CCN3C(=O)[O-])cc2)no1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(-c2ccc([C@H]3CNCCN3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Hydroxylamine hydrochloride (1.3 g, 20.2 mmol) and sodium carbonate (3.4 g, 32.1 mmol) were added to a solution of di-tert-butyl (2S)-2-(4-cyanophenyl)piperazine-1,4-dicarboxylate (2.5 g, 6.45 mmol) in ethanol (15 ml) and water (15 ml) at room temperature and the solution was stirred at 80° C. for 2 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Triethyl orthoacetate (10.5 g, 64.7 mmol) and p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol) were added to the solution of the residue in toluene (25 ml) and the solution was stirred at 90° C. for 2 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 10-20% ethyl acetate in hexane to furnish (2S)-2-(4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl)piperazine-1,4-dicarboxylate (1.0 g, 35%) as a colorless oil. Hydrogen chloride in ethyl acetate (4N) was added to a solution of (2S)-2-(4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl)piperazine-1,4-dicarboxylate (1.0 g, 2.25 mmol) in methanol and the mixture stirred at room temperature for one hour. The solvent was evaporated under reduced pressure to give a white solid, which was washed with ethyl acetate to afford (2S)-2-(4-(5-Methyl-[1,2,4]oxadiazol-3-yl)phenyl)piperazine dihydrochloride (0.64 g, 100%) as white crystals.
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:3].S(C1C=CC(C)=CC=1)(O[CH2:26][C:27]([F:30])([F:29])[F:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OC(=O)C)C>[OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:26][C:27]([F:30])([F:29])[F:28])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: C[C@H](O)[C@@H](CCc1ccccc1O)n1cnc(C(N)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](O)[C@@H](CCc1ccccc1OCC(F)(F)F)n1cnc(C(N)=O)c1
Temperature: 130 °C
Reaction time: 13 h
Yield: 54.5 %

Procedure:
A mixture of 1-[(2S,3R)-2-hydroxy-5-(2-hydroxyphenyl)-3-pentyl]imidazole-4-carboxamide (10 mg), 2,2,2-trifluoroethyl tosylate (27.4 mg) and potassium carbonate (14.9 mg) in N,N-dimethylformamide (1 ml) was stirred at 130° C. for 13 hours. The mixture was taken up in ethylacetate, washed three times with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (10:1) to give a pale brown powder of 1-{(2S,3R)-2-hydroxy-5-[2-(2,2,2-trifluoroethoxy)phenyl]-3-pentyl}imidazole-4-carboxamide (7) (7.0 mg).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:14](Cl)=[N:15][OH:16].[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([Cl:31])[CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]2([C:27]([F:30])([F:28])[F:29])[O:16][N:15]=[C:14]([C:3]3[CH:4]=[CH:5][C:6]4[B:7]([OH:13])[O:8][C:9]([CH3:12])([CH3:11])[C:10]=4[C:2]=3[F:1])[CH2:26]2)[CH:22]=[C:21]([Cl:31])[CH:20]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)c(F)c21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c(F)c21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of the crude compound 4-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (180 mg. 0.70 mmol) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (203 mg, 0.84 mmol) in DMF (5 mL) at rt was added TEA (117 μL, 0.84 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol[80 mg; yield 24.8% over the last 3 steps] as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.479 (s, 1H), 7.810 (t, J=1.5 Hz, 1H), 7.753 (t, J=7.5 Hz, 1H), 7.671 (d, J=1.5 Hz, 2H), 7.582 (d, J=7.5 Hz, 1H), 4.376 (d, J=18.0 Hz, 1H), 4.270 (d, J=18.0 Hz, 1H), 1.55 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=462.0 (M+1, ESI+).
Reaction SMILES: [O:1]=[CH:2][CH2:3][N:4]([C:18]1[C:19]2[CH:26]=[CH:25][N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:20]=2[N:21]=[CH:22][N:23]=1)[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1.[OH:37]O>CC#N.CCOC(C)=O>[C:14]([O:13][C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@@H:5]([N:4]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:28])=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][C:2]([OH:37])=[O:1])[CH2:6]1)=[O:12])([CH3:16])([CH3:17])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(CC=O)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Reactant: OO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(CC(=O)O)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of (R)-tert-butyl 3-((2-oxoethyl)(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (0.5 g, 0.97 mmol) in CH3CN (2 mL) at rt, was added an aq. solution of NaH2PO4 (3 mL, 0.21 g, 1.75 mmol), aq. NaO2Cl (2 mL, 0.16 g, 1.75 mmol) and 30% H2O2 (0.17 ml, 1.5 mmol) at 0° C. The reaction mixture was warmed to rt and stirred for overnight. The organic phase was concentrated in vacuo to afford a residue that was dissolved in EtOAc, filtered and dried over Na2SO4, concentrated in vacuo and purified by column chromatography (Silica gel, gradient MeOH: CH2Cl2) to afford the titled compound (0.105 g, 20.38%). LCMS [M+1]: 530.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]([O:34][CH3:35])=[O:33]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:24])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[CH:27][C:26]=1[Cl:25]
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 151, step 7) was reacted with 3-chloro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e)=530.1 [M+H+].
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:18][CH:19]=4)[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.I[CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH:24]5[CH2:29][CH2:28][N:27]([CH2:33][CH3:34])[CH2:26][CH2:25]5)=[CH:18][CH:19]=4)[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OC3CCNCC3)cc2c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN1CCC(Oc2ccc3ccn(-c4cc(C(=O)NC5CC5)ccc4C)c(=O)c3c2)CC1

Procedure:
N-Cyclopropyl-4-methyl-3-[1-oxo-7-(piperidin-4-yloxy)isoquinolin-2(1H)-yl]benzamide (50 mg), iodoethane (0.105 ml) and potassium carbonate (66 mg) were stirred in DMF (0.5 ml) at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water (5×), brine, dried (magnesium sulfate) and concentrated to give N-cyclopropyl-3-[7-[(1-ethylpiperidin-4-yl)oxy]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzamide as a cream coloured foam solid (44 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 1.00 (t, 3H), 1.69 (m, 2H), 1.99 (m, 2H), 2.10 (s, 3H), 2.25 (m, 2H), 2.38 (m, 2H), 2.71 (m, 2H), 2.85 (m, 1H), 4.53 (m, 1H), 6.70 (d, 1H), 7.20 (d, 1H), 7.41 (d, 1H), 7.49 (d, 1H), 7.67 (s, 1H), 7.70 (d, 1H), 7.72 (s, 1H), 7.88 (d, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 446.
Reaction SMILES: C([O-])([O-])=[O:2].[K+].[K+].[CH2:7]([NH:14][CH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=2)[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.OO>CS(C)=O>[CH2:7]([NH:14][C@H:15]1[CH2:16][CH2:17][C@H:18]([O:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]([NH2:27])=[O:2])=[CH:24][N:23]=2)[CH2:19][CH2:20]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(OC2CCC(NCc3ccccc3)CC2)nc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(O[C@H]2CC[C@H](NCc3ccccc3)CC2)nc1

Procedure:
Add K2CO3 (200 mg, 1.44 mmol) to a solution of 6-(4-benzylamino-cyclohexyloxy)-nicotinonitrile (890 mg, 2.89 mmol) in DMSO (25 mL). Cool the reaction to 0° C. and add hydrogen peroxide (0.87 mL). Stir the resulting reaction mixture at room temperature for 2 h. Then quench the reaction mixture with water (25 mL) and extract with EtOAc (30 mL). Dried over sodium sulfate, filter and concentrate. Further purify the residue by SCX chromatography to provide the title compound (700 mg, 74%). Mass spectrum (ion spray): m/z=326.0 (M+1); 1H NMR (CDCl3): 8.61 (s, 1H), 8.04 (m, 1H), 7.36 (m, 5H), 6.74 (d, J=8.8 Hz, 1H), 5.10 (m, 1H), 3.87 (s, 2H), 2.64 (m, 1H), 2.22–2.07 (m, 4H), 1.58–1.33 (m, 4H).