Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C[C:10]([CH3:12])=[O:11].C[OH:14]>>[C:10]([CH2:12][N:4]1[CH:3]=[C:2]([F:1])[CH:7]=[N:6][C:5]1=[O:8])([OH:14])=[O:11]
Reactant: CO
Reactant: CC(C)=O
Reactant: O=c1ncc(F)c[nH]1
Product: O=C(O)Cn1cc(F)cnc1=O
Yield: 67 %

Procedure:
Prepared as above from 5-fluoropyrimid-2-one in 67% yield, m.p. 200°-202° (decomp) (acetone/methanol). (Found: C, 41.80; H, 3.10. Calc. for C6H5FN2O3 : C, 41.87; H, 2.93).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[C:17]([CH2:19][NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]4[N:33]=[C:32](/[CH:34]=[C:35]5/[C:36](=[O:41])[NH:37][C:38](=[O:40])[S:39]/5)[CH:31]=[CH:30][N:29]=4)[CH2:23][CH2:22]3)[CH:16]=[CH:15][CH:14]=2)=[CH:9]1.CCN(C(C)C)C(C)C.Cl[C:52]([O:54][CH2:55]Cl)=[O:53]>CN(C=O)C.C([O-])(=O)C.[Ag+]>[C:3]([O:5][CH2:55][O:54][C:52](=[O:53])[N:20]([C@H:21]1[CH2:22][CH2:23][C@H:24]([NH:27][C:28]2[N:33]=[C:32](/[CH:34]=[C:35]3/[C:36](=[O:41])[NH:37][C:38](=[O:40])[S:39]/3)[CH:31]=[CH:30][N:29]=2)[CH2:25][CH2:26]1)[CH2:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][S:8][CH:9]=2)[N:18]=1)(=[O:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(Cl)OCCl
Reactant: O=C1NC(=O)/C(=C/c2ccnc(N[C@H]3CC[C@H](NCc4cccc(-c5ccsc5)n4)CC3)n2)S1
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCOC(=O)N(Cc1cccc(-c2ccsc2)n1)[C@H]1CC[C@H](Nc2nccc(/C=C3\SC(=O)NC3=O)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Z)-5-((2-((trans-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione trifluoroacetate salt (73.6 mg, 0.12 mmol, 1 equiv.) was dissolved in DMF (2 mL) and DIEA (63 μL, 0.36 mmol, 3 equiv.) was added at once. Chloromethyl chloroformate (10.7 μL, 0.12 mmol, 1.0 equiv.) was added at once and the reaction mixture was stirred at RT for 1 h. Silver acetate (61 mg, 0.36 mmol, 3 equiv.) was added at once and the reaction mixture was shaken for 1 h at 85° C. The desired carbamate was purified by preparative HPLC (TFA method). The purest fractions were pooled and evaporated. The residue was re-dissolved in a 1:1 mixture of methanol/1% NH4OH aqueous solution and the solvents were evaporated under reduced pressure. The free base was purified on silica gel (CH2Cl2/MeOH 95:5) to give the desired product as a yellow solid (1.1 mg, 73.7 mg theoretical, 1.5%). LC-MS m/z 609 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CS(C)=O>[CH2:15]([N:14]([CH2:19][CH2:20][CH2:21][CH3:22])[C:4]1[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=[C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:3]=1)[CH2:16][CH2:17][CH3:18]
Reactant: C1CNCCN1
Reactant: CCCCN(CCCC)c1nc(Cl)nc2c(SC)ncnc12
Solvent: CS(C)=O
Product: CCCCN(CCCC)c1nc(N2CCNCC2)nc2c(SC)ncnc12

Procedure:
Prepared analogously to Example 2 from 2-chloro-4-di-n-butylamino-8-methylthio-pyrimido[5,4-d]pyrimidine and piperazine in dimethylsulphoxide.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25](Cl)=[O:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25]([NH:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)=[O:26]
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: O=C(Cl)c1ccnc(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.2 %

Procedure:
A mixture of 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine (1.38 g, 5.07 mmol), 2-chloroisonicotinoyl chloride (1.34 g, 7.6 mmol), DIPEA (1.81 ml, 10.1 mmol) and THF (30 ml) is stirred at room temperature for 12 hours. The mixture is quenched with water (100 ml). The crude product is extracted with EtOAc (2×50 ml), the combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (3% MeOH in EtOAc) to afford 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide (1.07 g, 51%). 1H NMR (DMSO-d6) δ 10.61 (s, 1H), 8.62 (d, 1H), 8.21 (d, 1H), 8.10 (s, 1H), 7.95 (m, 2 H), 7.59 (d, 2 H), 7.49 (d, 1H), 7.09 (d, 1H), 4.33 (m, 2 H), 3.61 (m, 4 H), 2.92 (m, 2 H), 2.61 (m, 4 H). MS: 412 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[S:21][C:6]2[NH:7][C:8](=[O:20])[N:9]([CH2:12][C:13]3[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:40]=[C:39](C(Cl)(Cl)Cl)[O:38][N:37]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-:46].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:3]1[S:21][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:46])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:20])[N:9]([CH2:12][C:13]3[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCc1cc2c(=O)n(Cc3cnc(C)cn3)c(=O)[nH]c2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(Cc3cnc(C)cn3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.9 %

Procedure:
A mixture of 6-ethyl-3-[(5-methylpyrazin-2-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.3 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.47 g), potassium carbonate (0.27 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). 1N Aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 7 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.076 g, 14%).
Reaction SMILES: B1([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)OC(C)(C)C(C)(C)O1.I[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[N:27][C:28]=2[NH2:30])[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=[C:21]([C:10]3[CH:11]=[CH:12][C:13]([S:16]([NH2:19])(=[O:17])=[O:18])=[CH:14][CH:15]=3)[C:29]=12
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc(S(N)(=O)=O)cc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 9.5 %

Procedure:
A solution of benzenesulfonamide-4-boronic acid pinacol ester (23 mg, 0.08 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA14 (2.2 mg, 10% yield). ESI-MS (M+H)+ m/z calcd 333.1, found 333.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]([O:15]CC)=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[C:26]=2[OH:33])=[CH:21][CH:20]=1.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]([OH:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[C:26]=2[OH:33])=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1c(O)c2cc(-c3ccc(-c4cccc(OC)c4O)cc3)c(Cl)cc2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(-c3cc4c(O)c(C(=O)O)c(=O)[nH]c4cc3Cl)cc2)c1O
Temperature: 50 °C
Reaction time: 24 h
Yield: 17.7 %

Procedure:
To a suspension of ethyl 7-chloro-4-hydroxy-6-[2′-hydroxy-3′-(methyloxy)-4-biphenylyl]-2-oxo-1,2-dihydro-3-quinolinecarboxylate (Example 28) (150 mg, 0.322 mmol) in THF (4 mL) and water (2 mL) was added lithium hydroxide (100 mg, 2.4 mmol). The reaction mixture was stirred 48 h at 50° C. and 24 h at room temperature before being cooled down. The mixture was then evaporated, acidified with 1N HCl, filtered and dried. The resulting solid was triturated in hot acetonitrile, filtered and dried to give the title compound 7-chloro-4-hydroxy-6-[2′-hydroxy-3′-(methyloxy)-4-biphenylyl]-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid (25 mg, 0.057 mmol, 17.7% yield) as cream solid. LCMS: (M−H)+=436; Rt=2.89 min. HRMS: calculated for C23H15ClNO6 (M−H)+: 436.0588. found: 436.0560.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.Cl.Cl.[NH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:29])=[C:19]([CH:28]=1)[C:20]([NH:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)=[O:21].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[Cl:29][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:6]([C:3]2([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]2)=[O:7])=[CH:28][C:19]=1[C:20]([NH:22][C:23]1[NH:27][CH:26]=[CH:25][N:24]=1)=[O:21]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ncc[nH]1)c1cc(CNC(=O)C2(C(F)(F)F)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.5 %

Procedure:
To a suspension of 1-(trifluoromethyl)cyclopropanecarboxylic acid (54 mg, 0.34 mmol, 1.1 equiv) and 5-(aminomethyl)-2-chloro-N-(1H-imidazol-2-yl)benzamide dihydrochloride (100 mg, 0.31 mmol, 1.0 equiv) in THF (1.55 mL), add DIEA (0.189 mL, 1.08 mmol, 3.5 equiv), HOBt (59.2 mg, 0.386 mmol, 1.08 equiv), EDCI (74 mg, 0.386 mmol, 1.08 equiv), and stir the reaction mixture at room temperature for three days. Concentrate under reduced pressure, and subject the crude mixture to chromatography on a C18 reversed-phase stationary phase eluting with a 5-60% (0.1% TFA in acetonitrile) in (0.1% TFA in water) gradient to give the title compound as a white solid (39 mg, 33%). 1H NMR (DMSO-d6, 400 MHz): δ 11.80 (br s, 2H), 8.41 (t, 1H, J=5.8 Hz), 7.46 (d, 1H, J=8.3 Hz), 7.40 (d, 1H, J=2.1 Hz), 7.30 (dd, 1H, J=8.3, 2.1 Hz), 6.75 (br s, 2H), 4.28 (d, 2H, J=6.0 Hz), 1.33-1.20 (m, 4H). MS (m/z) (35Cl/37Cl) 387/389 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]2[C:12](=[C:14]([C:18]([OH:20])=O)[CH:15]=[CH:16][CH:17]=2)[N:13]=1.[ClH:22].Cl.[NH2:24][C@H:25]1[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:27]12[CH2:32][CH2:31][CH:30]([CH2:29][CH2:28]1)[C@H:25]([NH:24][C:18]([C:14]1[CH:15]=[C:16]([Cl:22])[CH:17]=[C:11]3[O:10][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]([CH3:1])[CH3:21])=[N:13][C:12]=13)=[O:20])[CH2:26]2
Reactant: Cl
Reactant: CN(C)c1ccccc1-c1nc2c(C(=O)O)cccc2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)c1ccccc1-c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cc(Cl)cc2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.6 %

Procedure:
A mixture of 2-(2-(dimethylamino)phenyl)benzo[d]oxazole-4-carboxylic acid (100 mg, 0.32 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (64 mg, 0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (123 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (1.5 mL) was stirred for 5 min at room temperature, then triethylamine (0.17 mL, 1.28 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford the (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamide (43 mg, 32%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.47 (d, J=7.5 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.97 (dd, J=8.0, 1.5 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.50-7.45 (m, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.02 (t, J=8.0 Hz, 1H), 4.28-4.25 (m, 1H), 3.49 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.08-2.84 (m, 4H), 2.84 (s, 6H), 2.76 (dd, J=14.0, 4.5 Hz, 1H), 2.13-2.10 (m, 1H), 1.99-1.94 (m, 1H), 1.76-1.68 (m, 2H), 1.58-1.52 (m, 1H); MS (ESI+) m/z 425 (M+H); HPLC>99% (AUC), tR=13.47 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH2:10])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:37]([OH:40])([CH3:39])[CH3:38].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:38][C:37](=[O:40])[CH3:39])=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH2:10])[CH:3]=1
Reactant: CC(C)O
Reactant: C=C(c1ccc(C)cc1)c1cc(Br)ccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(c1ccc(C)cc1)c1cc(Br)ccc1CC(C)=O
Temperature: 25 °C
Reaction time: 22.5 h

Procedure:
To a cold solution (0° C.) of 125 mg (0.4 mmol) of 4-bromo-2-[(1-p-tolyl)vinyl]phenol (Compound R) in 5 mL of tetrahydrofuran was added 125 mg (0.5 mmol) of triphenylphosphine and 0.04 mL (31 mg, 0.5 mmol) of isopropanol followed by 0.07 mL (82 mg, 0.5 mmol) of diethylazodicarboxylate. The dark yellow solution was removed from the ice bath, allowed to warm to ambient temperature on its own and stirred overnight (22.5 hours). The reaction mixture was concentrated in vacuo to a gummy yellow solid. Purification by flash chromatography (silica, 1% ethyl acetate in hexane) gave the title compound as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7](#[N:10])[CH:8]=[CH2:9]>CO>[C:7]([CH2:8][CH2:9][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])#[N:10]
Reactant: NCCCCN
Reactant: C=CC#N
Solvent: CO
Product: N#CCCNCCCCN
Yield: 79.8 %

Procedure:
To a solution of 1,4-diaminobutane (4.3 g, 48.8 mmole) in methanol (1.5 ml) was added a solution of acrylonitrile (3.1 g, 58.4 mmole) in methanol (1.5 ml) at 0° C., and the mixture was stirred for twelve hours. Evaporation of the solvent in vacuo afforded N-(2'-cyanoethyl)-1,4-diaminobutane as a colorless oil (5.5 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ: 1.45 (4H, br, --CH2 CH2 --), 2.46 (2H, t), 2.58 (2H, t), 2.62 (2H, t), 2.84 (2H, t).
Reaction SMILES: O[CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].C(N(CC)C(=O)OCN1CC(CCC)CC1=O)C.[Cl:30][C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>C(#N)C>[Cl:30][C:31]1[N:35]([CH2:2][N:3]2[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]2=[O:11])[C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCCC1CC(=O)N(CO)C1
Agent: CCCC1CC(=O)N(COC(=O)N(CC)CC)C1
Solvent: CC#N
Product: CCCC1CC(=O)N(Cn2c(Cl)nc3ccccc32)C1
Yield: 49.2 %

Procedure:
A solution of 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (0.472 g, 1 eq, 3 mmol), (2-oxo-4-propylpyrrolidin-1-yl)methyl diethylcarbamate x6 (38.5 mg, 5 mol %, 0.15 mmol) and 2-chloro-1H-benzimidazole x163 (1.2 eq, 3.3 mmol, 0.504 g) in acetonitrile (3 ml) is irradiated in a microwave apparatus (CEM discover) during 0.75 h (100 w). After cooling, evaporation of the solvent under reduce pressure and purification by preparative chromatography on reverse phase, 1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-propyl-pyrrolidin-2-one 300 is isolated as a clear oil (0.42 g).
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[Br-].[Li+].[CH3:11][C:12]([O:15][C:16]([N:18]1[C@@H:22]2[CH2:23][C:24]([CH2:26][C@H:19]1[CH2:20][CH2:21]2)=[O:25])=[O:17])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:15][C:16]([N:18]1[CH:19]2[CH2:20][CH2:21][CH:22]1[CH2:23][C:24]([OH:25])([CH3:4])[CH2:26]2)=[O:17])([CH3:11])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Reactant: CCOCC
Agent: C[Mg]Br
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(O)CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
A solution of methyl magnesium bromide in diethyl ether (3 M, 3.7 mL, 11.09 mmol) was diluted with anhydrous THF (5 mL). Lithium bromide (1.93 g, 22.1 mmol) was slowly added to the solution at rt, followed by addition of a solution of Boc-nortropinone (500 mg, 2.21 mmol) in anhydrous THF (5 mL). The reaction mixture was stirred at 50° C. for 2 hours and stirring was continued overnight at rt. The reaction was quenched with water and the mixture partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with a mixture of ethyl acetate and n-heptane (50:50), afforded 3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (168 mg, 31%). The obtained product was dissolved in 2 M HCl in diethyl ether (5 mL). After 4 hours stirring at rt the mixture was left on standing overnight. The formed participate, 3-methyl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride, was isolated by filtration and dissolved in a mixture of dichloromethane and methanol (90:10). PS-Trisamine was added to the solution and it was left standing overnight. The resin was removed by filtration and washed with dichloromethane. The filtrate was evaporated to dryness affording pure 3-methyl-8-azabicyclo[3.2.1]octan-3-ol. 1-Cyano-4-fluoronaphthalene (37.1 mg, 0.22 mmol) was added to a solution of 3-methyl-8-azabicyclo[3.2.1]octan-3-ol (91 mg, 0.64 mmol) in DMF (1 mL), followed by addition of pyridine (1 mL). The reaction mixture was stirred overnight at 100° C., cooled down to rt and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with a mixture of ethyl acetate and n-heptane (50:50), and by reverse phase preparative HPLC afforded the title compound (58 mg, 90%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[N:7]([O])[C:6]([CH3:10])([CH3:9])[CH2:5][CH2:4][CH2:3]1.[C:12]([O:16]N=O)(C)([CH3:14])[CH3:13].N[C:20]1[CH:25]=CC=C[CH:21]=1>N1C=CC=CC=1.[Co]>[O:16]([N:7]1[C:2]([CH3:11])([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1([CH3:10])[CH3:9])[C:12]1[CH:14]=[CH:25][CH:20]=[CH:21][CH:13]=1
Reactant: CC1(C)CCCC(C)(C)N1[O]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)ON=O
Agent: [Co]
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1Oc1ccccc1
Yield: 72.7 %

Procedure:
The procedure of Example 5 is repeated using 1.95 g (12.5 mmol) of 2,2,6,6-tetramethylpiperidine-1-oxyl, 3.09 g (30.0 mmol) of tert-butylnitrite and 378 mg (˜0.125 mmol) of cobalt polyoxometallate (K7PCoW11O39•H2O) in 100 mL of pyridine and 2.32 g (25 mmol) of aniline in 5 mL of pyridine. The crude is purified by vacuum flash chromatography (heptane) to give 2.12 g of a colorless oil in 72.8% yield.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[S:12]1[C:16]([NH2:17])=[CH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2>N1C=CC=CC=1>[S:12]1[C:16]([NH:17][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2
Reactant: Nc1cc2ccccc2s1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc2ccccc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzenesulfonyl chloride (0.661 mL, 5.15 mmol) was added to a solution of compound 1-C (0.87 g, 4.69 mmol) in pyridine (10 mL) at 0° C. The ice bath was removed and the solution was stirred at ambient temperature for 2 h. The solvent was evaporated in vacuo, and the residue was partitioned between 2 N HCl and dichloromethane. The organic layer was dried over magnesium sulfate and the solvent evaporated in vacuo. The residue was pre-absorbed on silica gel and purified by flash column chromatography, eluting with a gradient of ethyl acetate (10-50%) in heptane, to afford compound 1-D as a colorless solid (1.19 g, 88%). 1H-NMR (CDCl3): δ 6.96 (s, 1H), 7.25-7.34 (m, 2H), 7.44-7.49 (m, 2H), 7.55-7.66 (m, 3H), 7.84-7.88 (m, 2H); MS: m/z 290.1 (MH+).
Reaction SMILES: C([O:8][C:9]1[C:10]([O:28][CH3:29])=[CH:11][C:12]([CH:26]=O)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][C:16]=2[O:24][CH3:25])[CH:14]=1)C1C=CC=CC=1.C(OC(=O)[NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)(C)(C)C.[CH2:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>C(#N)C>[NH2:36][CH2:37][C:38]1[CH:39]=[C:40]2[C:41](=[CH:42][CH:43]=1)[NH:44][CH:26]([C:12]1[CH:11]=[C:10]([O:28][CH3:29])[C:9]([OH:8])=[CH:14][C:13]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][C:16]=1[O:24][CH3:25])[CH:47]1[CH2:48][C:49]3[C:54]([CH:46]21)=[CH:53][CH:52]=[CH:51][CH:50]=3
Reactant: COc1cc(C=O)c(-c2ccc(C(=O)O)cc2OC)cc1OCc1ccccc1
Reactant: C1=Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Solvent: CC#N
Product: COc1cc(C2Nc3ccc(CN)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2OC)cc1O
Temperature: 75 °C

Procedure:
To a suspension of 5′-Benzyloxy-2′-formyl-2,4′-dimethoxy-biphenyl-4-carboxylic acid (50 mg, 0.127 mmol) and (4-Amino-benzyl)-carbamic acid tert-butyl ester (28 mg, 0.127 mmole) in 2 ml dry acetonitrile was added 30μl of indene and a catalytic amount of In(OTf)3. The reaction was sealed and heated at 75° C. for 16 h. The reaction was then allowed to cool to room temperature and then purified by HPLC. Mass spectrum 505 (M−17); in the presence of 0.1M ammonium acetate 521 (M−1) observed for negative ion mode.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([F:12])[C:9]([CH3:11])=[N:10][C:5]2=[N:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][C:15]=1[C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:6]3[CH:7]=[C:8]([F:12])[C:9]([CH3:11])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:16][C:15]=1[C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1nc2ncc(Br)n2cc1F
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: Cc1nc2ncc(-c3ccc(F)c(-c4ccccc4C#N)c3)n2cc1F
Yield: 58 %

Procedure:
3-Bromo-6-fluoro-7-methylimidazo[1,2-α]pyrimidine (24 mg, 0.50 mmol) was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-(6-fluoro-7-methylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile (21 mg, 58%) as a white powder: δH (400 MHz, CDCl3) 2.67 (3H, d, J 3), 7.39-7.43 (1H, m), 7.53-7.62 (4H, m), 7.69-7.74 (1H, m), 7.84 (1H, d, J 1), 7.86 (1H, s), 8.67 (1H, d, J 5); m/z (ES+) 347 (M++H).