Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:36]=[CH:35][CH:34]=[CH:33][C:14]=3[C:15]([NH:17][CH:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:19]([OH:25])[C:20]([O:22]CC)=[O:21])=[O:16])[N:9]=2)=[CH:4][CH:3]=1.O1CCCC1.C(Cl)Cl.CO>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:36]=[CH:35][CH:34]=[CH:33][C:14]=3[C:15]([NH:17][CH:18]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:19]([OH:25])[C:20]([OH:22])=[O:21])=[O:16])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a suspension of ethyl 3-(2-(3-(4-fluorophenyl)-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-phenylbutanoate (4500 mg, 9.21 mmol) in tetrahydrofuran (THF) (500 ml) lithium hydroxide (LiOH) (441 mg, 18.42 mmol) in water (100 ml) was added, and the mixture stirred for 2 h at room temperature. After completion of the reaction (tlc: CH2Cl2+10% (v/v) methanol) the mixture was concentrated under reduced pressure and after addition of water (300 ml) acidified using 2 n HCl. The precipitate formed was filtered off and dried to give 4.13 g of a white amorphous solid.
Reaction SMILES: C[Mg]Cl.[Cl:4][C:5]1[CH:6]=[C:7](Cl)[C:8]2[C:9](=[CH:11][S:12][CH:13]=2)[N:10]=1.[CH3:15]N1CCCC1=O>C1COCC1.O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[Cl:4][C:5]1[CH:6]=[C:7]([CH3:15])[C:8]2[C:9](=[CH:11][S:12][CH:13]=2)[N:10]=1
Reactant: CN1CCCC1=O
Reactant: Clc1cc(Cl)c2cscc2n1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc2cscc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution (0.67 mL) of 3 M methyl magnesium chloride in THF was added dropwise to a mixture of 2,4-dichlorothieno[3,4-b]pyridine (0.37 g), iron(III) acetylacetonate (0.064 g), N-methyl-2-pyrrolidinone (1 mL), and THF (15 mL) with ice cooling, and the mixture was stirred at room temperature for 20 h. The reaction solution was diluted with water, and the mixture was extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel and NH silica gel, ethyl acetate/hexane=20:1-10:1) to obtain 2-chloro-4-methylthieno[3,4-b]pyridine (0.027 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Cl:13].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:16])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Cl:13]
Reactant: Cn1ncc(Cl)c1-c1sc(C(=O)O)cc1Cl
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1Cl
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a solution of 4-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (136.1 mg, 0.49 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (179 mg, 0.51 mmol)[prepared according to Preparation 6], diisopropylethyl amine (260 uL, 1.5 mmol) in DCM (5 mL) was added PyBrop (341 mg, 0.75 mmol) in one portion. After 1 h, the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, gradient 0-50% ethyl acetate/hexane) affording the title compound (242 mg, 82%) as a white solid: LCMS (ES) m/z=607 (M+H)+.
Reaction SMILES: C(O)C.[Br-].[Li+].[CH2:6]([O:13][C:14]([NH:16][C@@H:17]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:18]([OH:25])[C:19](OC(C)C)=[O:20])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+]>O1CCCC1.O>[CH2:6]([O:13][C:14]([NH:16][C@@H:17]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:18]([OH:25])[CH2:19][OH:20])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)OC(=O)C(O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(O)CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethanol (1 ml) and lithium bromide (36.7 mg) are added to a solution of isopropyl (2RS,3S)-3-(benzyloxycarbonyl)amino-2-hydroxy-4-phenylbutyrate (150 mg, Reference compound No. 13-1) in tetrahydrofuran (1 ml). The mixture is cooled with ice, sodium borohydride (42.1 mg) is added to the mixture, and the temperature is raised to room temperature. The whole is stirred overnight, water is added thereto, and the whole is further stirred for one hour. The reaction mixture is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure to give the titled reference compound (105 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Br[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[C:25]=1[C:32]([F:35])([F:34])[F:33].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.[Li+].[Cl-].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:31][C:26]1[C:25]([C:32]([F:35])([F:33])[F:34])=[C:24]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1F
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: [Cl-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)c(F)c2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 87.8 %

Procedure:
A mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (6, 57.4 g, 185 mmol), 3 1-bromo-3,4-difluoro-2-(trifluoromethyl)benzene (48.5 g, 185 mmol), Pd(PPh3)4 (21.5 g, 18.5 mmol), and 2 M Na2CO3 (150 mL) in DME (500 mL) was heated to 80° C. for 16 h. The mixture cooled to ambient temperature and was diluted with 5% aqueous LiCl solution (100 mL). The mixture was extracted with EtOAc (3×200 mL), and the combined organic extracts were washed with brine (2×200 mL) and concentrated under reduced pressure. The residue was diluted in CH2Cl2 (100 mL) and sent through a 300 mL silica gel plug, eluting with 10% EtOAc in hexanes (800 mL). The resulting filtrate was concentrated under reduced pressure and was chromatographed over silica gel (Isco CombiFlash Rf unit, 3×330 g Redisep columns, 0% to 50% EtOAc in hexanes) to provide tert-butyl 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (7) as a white solid (59.0 g, 92%): 1H NMR (300 MHz, CDCl3) 57.34-7.28 (m, 1H), 6.93 (m, 1H), 5.55 (br, 1H), 4.01 (br, 2H), 3.60 (m, 2H), 2.30 (m, 2H), 1.50 (s, 9H); MS (ESI+) m/z 308 [M+H−C4H8]+.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][N:7]=2)[OH:5])[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(=O)(O)[O-]>[CH:1]1([C:4]([C:6]2[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][N:7]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: OC(c1n[nH]c2ncccc12)C1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=C(c1n[nH]c2ncccc12)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
Cyclopropyl(1H-pyrazolo[3,4-b]pyridin-3-yl)methanol (200 mg, 1.06 mmol) was taken up in DCM (8 mL). Dess-Martin (0.448 g, 1.06 mmol) was added to this solution, which was stirred at room temperature for 10 minutes. A solution of 10% sodium thiosulfate in saturated aqueous bicarbonate was added and resulted in a biphasic solution, which was vigorously stirred for 30 minutes. The organic layers were extracted with DCM (3×10 mL), dried over sodium sulfate and concentrated. Chromatography (EtOAc) afforded cyclopropyl(1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (100 mg, 50.5%) as an oil, which crystallized upon standing.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CO>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[O:17][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(Br)c(OCc3ccccc3)c2s1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
A mixture of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 6 (0.050 g, 0.16 mmol) and potassium carbonate (0.023 g, 0.17 mmol, 1.05 eq) in anhydrous DMF (1.6 mL) was stirred at about 20° C. for about 0.5 hour, and was cooled down to about 0° C. The reaction mixture was treated with benzyl bromide (0.019 mL, 0.16 mmol, 1.0 eq), and was stirred at about 0° C. for about 16 hours. To the reaction mixture was added methanol (10 mL). The solid was filtered off and rinsed with methanol (3 mL). The solvent was evaporated and the residue was dissolved in DMF (2 mL). The crude reaction solution was purified by LC/MS to give 0.029 g (45%) of the desired compound 9. 1H NMR (DMSO) δ 10.86 (br s, 1H, NH), 7.59–7.34 (m, 7H, ArH), 6.72 (br s, 1H, NH), 5.17 (s, 2H, CH2), 3.18 (m, 2H, CH2), 1.09 (t, 3H, J=7.2 Hz, CH3); LC/MS 406 (MH+); RP-HPLC RT 3.8 minutes.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:31])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:16][C:17]([OH:19])=O)[C:9]2=[O:14])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:44]([NH:46][NH2:47])=O.P(Cl)(Cl)(Cl)=O>C(#N)C.CCOCC.O>[CH2:29]([O:28][C:22]1[CH:21]=[C:20]([CH:15]([N:8]2[C:7](=[O:31])[C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[NH:4][C:1](=[O:3])[CH3:2])[C:9]2=[O:14])[CH2:16][C:17]2[O:19][CH:44]=[N:46][N:47]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH3:30]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCOc1cc(C(Cc2nnco2)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
A mixture of 3-[4-(acetylamino)-1,3-dioxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (1.69 g, 3.96 mmol) and carbonyidiimidazole (0.71 g, 4.4 mmol) in acetonitrile (20 mL) was stirred at room temperature for 2 hours. To the solution was added formic hydrazide (289 mg, 4.81 mmol). The mixture was then stirred for 18 hours. To the resulting solution was added phosphorus oxychloride (1.0 mL, 10.7 mmol), and this mixture was heated at reflux for 2 hours. The solution was poured to water (10 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with aqueous sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and then dried over magnesium sulfate. Chromatography followed by removal of solvent yielded an oil. The oil was stirred in ether (10 mL) to give a suspension. This suspension was filtered to yield N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]-1,3-dioxoisoindolin-4-yl]acetamide as a white solid (478 mg, 27% yield): mp, 141.0-143.0° C.; 1H NMR (CDCl3) δ 1.47 (t, J=6.9 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 3.74 (dd, J=5.8, 15.8 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.11 (q, J=7.1 Hz, 2H, CH2), 4.38 (dd, J=10.6, 15.8 Hz, 1H, CHH), 5.78 (dd, J=5.6, 10.6 Hz, 1H, NCH), 6.83 (d, J=8.9 Hz, 1H, Ar), 7.11-7.14 (m, 2H, Ar), 7.45 (d, J=7.2 Hz, 1H, Ar), 7.64 (d, J=7.5 Hz, 1H, Ar), 8.31 (s, 1H, Ar), 8.75 (d, J=8.4 Hz, 1H, Ar), 9.46 (br s, 1H, NH); 13C NMR (CDCl3) δ 14,70, 24.92, 27.60, 51.74, 55.92, 64.50, 111.40, 112.47, 115.15, 118.11, 120.15, 124.91, 129.87, 130.99, 136.01, 137.55, 148.49, 149.59, 153.07, 163.88, 167.44, 169.14, 169.75; Anal Calcd for C23H22N4O6: C, 61.33; H, 4.92; N, 12.44. Found: C, 61.37; H, 4.88; N, 12.11.
Reaction SMILES: [Cl:1][C:2]1[C:3](C(N)=O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([NH:16][C:17]([C:19]2[C:20](=[O:32])[N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:22]([CH3:25])[C:23]=2[CH3:24])=[O:18])=[CH:11][C:10]=1[F:33].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.CC#[N:54]>CCOC(C)=O.O>[NH2:54][C:3]1[C:2]([Cl:1])=[C:7]([O:8][C:9]2[C:10]([F:33])=[CH:11][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:22]([CH3:25])[C:23]=3[CH3:24])=[O:18])=[C:13]([F:15])[CH:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(C(N)=O)c3Cl)cc2F)c(=O)n(-c2ccccc2)n1C
Reactant: CC#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(N)c3Cl)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a suspension of 3-chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2,5-difluorophenoxy)picolinamide (310 mg, 0.60 mmol) in EtOAc (6.0 mL), CH3CN (6.0 mL) and H2O (3.0 mL) at 0° C. was added iodobenzene diacetate (234 mg, 0.72 mmol). After stirring at 0° C. for 30 minutes, the mixture was allowed warm up to rt and stirred for 4 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (MeOH/DCM (v/v)=1/70) to give the title compound as a pale yellow solid (200 mg, 69%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].I[CH:37]([CH3:39])[CH3:38]>CN(C=O)C.CC(C)=O>[CH3:38][CH:37]([N:27]1[N:28]=[N:29][C:25]([N:22]2[CH2:23][CH2:24][CH:19]([CH2:18][O:17][C:14]3[CH:15]=[CH:16][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=4)=[N:12][CH:13]=3)[CH2:20][CH2:21]2)=[N:26]1)[CH3:39]
Reactant: CC(C)I
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(c4nnn[nH]4)CC3)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1nnc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
A solution of 2-[4-(methylsulfonyl)phenyl]-5-({[1-(1H-tetrazol-5-yl)-4-piperidinyl]methyl}oxy)pyridine (157 mg, 0.38 mmol) in DMF (2 mL) and acetone (3 mL) was added potassium carbonate (105 mg, 0.76 mmol) at room temperature. After stirring for 15 min, 2-iodopropane (193 mg, 1.14 mmol) was added by syringe and the mixture was heated at 50° C. for 16 h. The salt was removed by filtration and washed with MeOH/CH2Cl2. After concentration, a small amount of MeOH/CH2Cl2 was added and the resulting precipitate was collected and washed with a small amount of MeOH. The material was dried in vacuo to give the title compound (130 mg, 71%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (d, 1H, J=2.9 Hz), 8.34-8.25 (m, 2H), 8.07 (d, 1H, J=8.8 Hz), 7.99 (d, 2H, J=8.7 Hz) 7.55 (dd, 1H, Ja=8.8 Hz, Jb=2.9 Hz), 4.88 (septet, 1H, J=6.7 Hz), 4.03 (d, 2H, J=6.6 Hz), 3.98 (d, 2H, J=12.6 Hz), 3.25 (s, 3H), 3.01-2.86 (m, 2H), 2.11-1.95 (m, 1H), 1.94-1.82 (m, 2H), 1.50 (d, 6H, J=6.7 Hz), 1.46-1.30 (m, 2H); LRMS (ESI), m/z 457 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](=[O:8])O[C:4](=[O:9])[CH2:3]1.[F:10][C:11]([F:16])([F:15])[C:12]([O-:14])=[O:13].[Cl:17][C:18]1[N:22]2[C:23]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:36])=[C:33]([NH3+:35])[CH:34]=3)=[CH:24][NH:25][C:26](=[O:27])[C:21]2=[CH:20][C:19]=1[Cl:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.O.CC#N>[F:10][C:11]([F:16])([F:15])[C:12]([O-:14])=[O:13].[Cl:17][C:18]1[N:22]2[C:23]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:36])=[C:33]([N:35]4[C:4](=[O:9])[CH2:3][NH+:2]([CH3:1])[CH2:7][C:6]4=[O:8])[CH:34]=3)=[CH:24][NH:25][C:26](=[O:27])[C:21]2=[CH:20][C:19]=1[Cl:37]
Reactant: CN1CC(=O)OC(=O)C1
Reactant: [NH3+]c1cc(Cc2c[nH]c(=O)c3cc(Cl)c(Cl)n23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: O
Product: C[NH+]1CC(=O)N(c2cc(Cc3c[nH]c(=O)c4cc(Cl)c(Cl)n34)ccc2F)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methylmorpholine-2,6-dione (1 eq) (see for Ref. WO 03/093261) in toluene (0.06 M) was added N2 (Example 14, step 2). The reaction mixture was refluxed for 2 h and then allowed to stand at RT overnight. The solvent was removed under reduced pressure. The resulting crude was dissolved in DMF (0.2 M) and to the resulting solution were added sequentially TBTU (1.3 eq), DIPEA (2.2 eq) and DMAP (0.3 eq). The mixture was stirred at RT for 2 h and then the product was isolated by purification at prep RP-HPLC using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). The desired fractions were lyophilized to afford the desired compound as a white powder. 1H NMR (400 MHz, DMSO-d6+TFA) δ: 7.41-7.27 (2H, m), 7.14 (1H, s), 7.08 (1H, d, J=6.8 Hz), 6.59 (1H, br. s), 4.38 (2H, s), 4.25 (4H, m), 2.85 (3H, s). MS (ES) C19H15Cl2FN4O3 requires: 436/438, found: 437/439 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].FC1C=[C:17]([C:23]#[N:24])[CH:18]=[C:19]([CH:22]=1)[C:20]#N.C(Cl)(=O)C1C=CC=NC=1.N>>[F:13][C:11]1[CH:12]=[C:3]([CH:4]=[C:5]([C:6]2[N:7]=[C:22]([C:19]3[CH:20]=[N:24][CH:23]=[CH:17][CH:18]=3)[O:9][N:8]=2)[CH:10]=1)[C:1]#[N:2]
Reactant: N#Cc1cc(F)cc(C#N)c1
Reactant: N#Cc1cc(F)cc(C(N)=NO)c1
Agent: N
Agent: O=C(Cl)c1cccnc1
Product: N#Cc1cc(F)cc(-c2noc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared according to the procedure of Example 4B using 3-cyano-5-fluoro-N′-hydroxybenzimidamide (Prepared from 5-fluoroisophthalonitrile using the procedure described in Example 4A) and nicotinoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.77 (m, 1H), 8.2 (m, 2H), 8.4 (m, 1H), 8.6 (m, 1H), 8.9 (m, 1H), 9.4 (m, 1H) ppm; MS (DCl/NH3) m/z 267 (M+H)+.
Reaction SMILES: [OH2:1].O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[OH:27])([CH3:17])([CH3:16])[CH3:15]>S(=O)(=O)(O)O.O.C(OCC)C>[C:14]([C:18]1[C:19](=[O:27])[C:20]([CH:24]([CH3:25])[CH3:26])=[CH:21][C:22](=[O:1])[CH:23]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)c1cccc(C(C)(C)C)c1O
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reaction time: 2.5 h

Procedure:
A 160 g quantity of sodium dichromate dihydrate was dissolved in a mixture of 100 ml of 97% sulfuric acid and 230 ml of water, and the solution was added to a solution of 45.0 g of 2-tert-butyl-6-isopropylphenol in 350 ml of diethyl ether with stirring at a temperature of 5°-10° C.over a period of 2.5 hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed serially with asaturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent: diethyl ether-hexane=1:10), giving 12.7 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)=[CH:7][C:4]=1[CH:5]=[O:6].CC(=CC)C.Cl([O-])=[O:31].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+]>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)=[CH:7][C:4]=1[C:5]([OH:31])=[O:6]
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C=O
Agent: CC=C(C)C
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C(=O)O
Yield: 108.7 %

Procedure:
2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde (1.00 g) was dissolved in tert-butanol (24 mL). To the mixture was added 2-methyl-2-butene (6 mL) at room temperature with stirring. After adding sodium chlorite (553 mg) and an aqueous solution of sodium hydrogen phosphate (250 g/L, 12 mL), the mixture was stirred at room temperature for 2 days, and then extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.14 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:17]([C:19]3[O:20][C:21](=[O:35])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:18])[N:9]=[C:10](C3C=NC=CN=3)[C:3]=12.[F:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([NH:46][C:47]2[CH:48]=[N:49][CH:50]=[C:51]([Sn](C)(C)C)[CH:52]=2)(=[O:45])=[O:44])=[CH:39][CH:38]=1.NC1N=CN=C2N(C(C3OC(=O)C4C(C=3C3C=CC=CC=3)=CC=CC=4)C)N=C(I)C=12>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:17]([C:19]3[O:20][C:21](=[O:35])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:18])[N:9]=[C:10]([C:51]3[CH:52]=[C:47]([NH:46][S:43]([C:40]4[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=4)(=[O:45])=[O:44])[CH:48]=[N:49][CH:50]=3)[C:3]=12
Reactant: C[Sn](C)(C)c1cncc(NS(=O)(=O)c2ccc(F)cc2)c1
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnccn2)c2c(N)ncnc21
Agent: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cncc(NS(=O)(=O)c3ccc(F)cc3)c2)c2c(N)ncnc21
Yield: 17.4 %

Procedure:
The title compound was made in a similar way as that of the compound of example 52 from 4-fluoro-N-(5-(trimethylstannyl)pyridin-3-yl)benzenesulfonamide (Intermediate G9, 98 mg, 0.236 mmol) and 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (intermediate D2a, 60 mg, 0.118 mmol) affording the title compound (13 mg, 0.021 mmol, 17.4% yield) as white solid