Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C=O)C>[C:25]1([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][C@H:18]([NH:17][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:19]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C(c1ccccc1)c1ccccc1
Yield: 56.9 %

Procedure:
Diphenylacetic acid (0.75 g) and (S)-3-amino-1-(2-phenylethyl)pyrrolidine (0.67 g) were dissolved in DMF (10 ml), and triethylamine (1.4 ml) was added thereto, which was followed by addition of diethyl cyanophosphate (0.67 ml) under ice-cooling. After completion of the reaction, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed successively with an aqueous potassium carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:methanol=30:1). The obtained eluate was concentrated to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)diphenylacetamide (0.77 g). The obtained compound was dissolved in acetone (3 ml), and a solution of oxalic acid (0.18 g) in acetone (3 ml) was added thereto. The precipitated crystals were collected by filtration and washed with acetone to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)diphenylacetamide oxalate, melting point 191-192° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:5]=[N:6][C:7]=1[Cl:8].C([Sn](CCCC)(CCCC)[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC>C1(C)C=CC=CC=1>[Cl:8][C:7]1[N:6]=[CH:5][C:4]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])=[CH:3][C:2]=1[C:25]1[CH:24]=[N:23][CH:22]=[N:27][CH:26]=1
Reactant: CN1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1cnc(Cl)c(-c2cncnc2)c1
Yield: 49.9 %

Procedure:
To the solution of 5-bromo-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)-pyridine (390 mg, 1.27 mmol) in toluene (15 mL) was added tetrekis(triphenylphosphine)palladium (40 mg, 1%) and tributyl(pyrimidinyl)tin (0.57 g, 1.53 mmol). The mixture was stirred and heated under reflux for 6 h. Solvent was evaporated and the residue was chromatographed (silica gel; CH2Cl2 /MeOH, 10:0.3 to 10:1) to afford an oil (193 mg, 50%): 1H NMR (CDCl3, 300 MHz) δ 1.62 (m, 1H), 1.68-1.90 (m, 2H), 2.02 (m, 1H), 2.32 (m, 1H), 2.50 (s, 3H), 2.70 (m, 1H), 3.12 (m, 1H), 3.98-4.06 (m, 2H), 7.25 (m, 1H), 8.18 (d, 1H, J=3.0 Hz), 8.87 (s, 2H), 9.29 (s, 1H); MS (CI/NH3) m/z 305 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH:16]([CH:18]4[CH2:20][CH2:19]4)[C:15](=[O:21])[NH:14][C:13]=3[CH:22]=2)[C:5]([F:23])=[CH:4][N:3]=1.[OH:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[CH2:19]1[CH2:20][CH:18]1[CH:16]1[C:15](=[O:21])[NH:14][C:13]2[CH:22]=[C:9]([NH:8][C:6]3[C:5]([F:23])=[CH:4][N:3]=[C:2]([NH:28][C:27]4[CH:29]=[CH:30][CH:31]=[C:25]([OH:24])[CH:26]=4)[N:7]=3)[CH:10]=[CH:11][C:12]=2[O:17]1
Reactant: O=C1Nc2cc(Nc3nc(Cl)ncc3F)ccc2OC1C1CC1
Reactant: Nc1cccc(O)c1
Product: O=C1Nc2cc(Nc3nc(Nc4cccc(O)c4)ncc3F)ccc2OC1C1CC1

Procedure:
In like manner to the preparation of N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamine and 3-hydroxyaniline were reacted to yield the desired product N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.09 (d, 1H), 7.23 (m, 2H), 7.01 (m, 3H), 6.82 (d, 1H), 6.39 (m, 1H), 1.20 (m, 4H); LCMS: retention time 9.30 min; purity 96%; MS (m/e): 394 (MH+).
Reaction SMILES: C(OCCC[N:7]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=3)=[CH:17][C:12]=2[CH:11]=[C:10]([C:31](O)=[O:32])[CH2:9][CH2:8]1)C.S(Cl)(Cl)=O.C[N:39](C=O)C>C1COCC1>[CH2:28]([O:27][CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[CH:15]=[CH:14][C:13]3[NH:7][CH2:8][CH2:9][C:10]([C:31]([NH2:39])=[O:32])=[CH:11][C:12]=3[CH:17]=2)=[CH:19][CH:20]=1)[CH2:29][CH3:30]
Reactant: CN(C)C=O
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOCC)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(N)=O)CCN3)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(3-ethoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (250 mg) in THF (10 ml) were added thionyl chloride (0.080 ml) and DMF (one droplet) at room temperature, and the mixture was stirred for 1.5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in THF (20 ml), which was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (133 mg) and triethylamine (0.46 ml) in THF (3 ml) at 0° C. The mixture was stirred at room temperature for 2.5 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was purified with column chromatography (ethanol:ethyl acetate=1:9→1:3), and the resulting crystals were purified by recrystallization (hexane-ethyl acetate) to give 1-(3-ethoxypropyl)-N-[4-[[N-methyl-N-tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 105) (242 mg) as yellow crystals.
Reaction SMILES: [CH2:1]1N2C(=O)N3C4N5C(=O)N(C[N:59]6[C:60]([N:62]7[CH2:63][N:64]8[C:65]([N:67]9[CH2:68][N:69]%10[C:70]([N:72]%11[CH2:73][N:74]%12[C:75]([N:77]%13[CH2:78][N:79]%14[C:80]([N:82]%15[CH2:83][N:84]%16[C:85]([N:87]%17[CH2:88]N%18C(N(C5)C5N(C3)C(=O)N(C5%18)C[N:40]3[C:41](=[O:42])[N:37]([CH:38]%16[CH:39]3%17)[CH2:36][N:33]3[C:34](=[O:35])[N:30]([CH:31]%14[CH:32]3%15)[CH2:29][N:26]3[C:27](=[O:28])[N:23]([CH:24]%12[CH:25]3%13)[CH2:22][N:19]3[C:20](=[O:21])[N:16]([CH:17]%10[CH:18]3%11)[CH2:15][N:12]3[C:13](=[O:14])[N:9]([CH:10]8[CH:11]39)[CH2:8][N:5]3[C:6](=[O:7])[N:2]1[CH:3]6[CH:4]37)=O)=[O:86])=[O:81])=[O:76])=[O:71])=[O:66])=[O:61])C42>O>[CH2:22]1[N:23]2[C:27](=[O:28])[N:26]3[CH:25]4[N:77]5[C:75](=[O:76])[N:74]([CH2:73][N:72]6[C:70]([N:69]7[CH2:68][N:67]8[C:65]([N:64]9[CH2:63][N:62]%10[C:60]([N:59]%11[CH2:88][N:87]%12[C:85]([N:84]%13[CH2:83][N:82]%14[C:80]([N:79]([CH2:78]5)[CH:31]5[N:30]([CH2:29]3)[C:34](=[O:35])[N:33]([CH:32]5%14)[CH2:36][N:37]3[C:41](=[O:42])[N:40]([CH:39]%12[CH:38]3%13)[CH2:1][N:2]3[C:6](=[O:7])[N:5]([CH:4]%10[CH:3]3%11)[CH2:8][N:9]3[C:13](=[O:14])[N:12]([CH:11]8[CH:10]39)[CH2:15][N:16]3[C:20](=[O:21])[N:19]1[CH:18]6[CH:17]37)=[O:81])=[O:86])=[O:61])=[O:66])=[O:71])[CH:24]42
Reactant: O=C1N2CN3C(=O)N4CN5C(=O)N6CN7C(=O)N8CN9C(=O)N%10CN%11C(=O)N%12CN%13C(=O)N%14CN%15C(=O)N%16CN1C1C2N2CN%17C(=O)N(CN%18C(=O)N(CN%19C(=O)N(CN%20C(=O)N(CN%21C(=O)N(CN%22C(=O)N(CN%23C(=O)N(CN1C2=O)C%16C%15%23)C%14C%13%22)C%12C%11%21)C%10C9%20)C8C7%19)C6C5%18)C4C3%17
Solvent: O
Product: O=C1N2CN3C(=O)N4CN5C(=O)N6CN7C(=O)N8CN9C(=O)N%10CN%11C(=O)N%12CN1C1C2N2CN%13C(=O)N(CN%14C(=O)N(CN%15C(=O)N(CN%16C(=O)N(CN%17C(=O)N(CN1C2=O)C%12C%11%17)C%10C9%16)C8C7%15)C6C5%14)C4C3%13

Procedure:
Here, the alkylimidazolium compound forms a complex with CB[8]. The complex is preferably water soluble, thereby to allow separation from CB[6], which is insoluble in water.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[CH:11]1([C:16](=O)[CH2:17][C:18]#[N:19])[CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH:11]1([C:16]2[CH:17]=[C:18]([NH2:19])[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH3:2])[N:10]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N#CCC(=O)C1CCCC1
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccccc1-n1nc(C2CCCC2)cc1N
Yield: 62 %

Procedure:
A solution of (2-methylphenyl)hydrazine hydrochloride (2.00 g, 14.6 mmol) and crude 3-cyclopentyl-3-oxopropanenitrile from the previous step (2.32 g, ˜14.6 mmol) in toluene (6 mL) was heated to reflux for 16 h. Removal of the solvent under reduced pressure provided a residue which was purified by silica gel chromatography using hexane/EtOAc (3:1, v/v) as the eluent. Concentration under reduced pressure provided 3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-amine as a light orange solid (2.19 g, 62%). 1H NMR (400 MHz, CDCl3) δ 1.58-1.82 (m, 6H), 2.00-2.16 (m, 2H), 2.17-2.21 (s, 3H), 2.93-3.11 (m, 1H), 3.42-3.58 (s, 2H), 5.41-5.46 (s, 1H), 7.20-7.28 (m, 2H) 7.29-7.37 (m, 2H); ES-MS m/z 241.9 (MH+); HPLC RT (min) 1.69.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([N:9]1[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:19][CH3:20])[C:10]1=[O:21])[CH2:2]2>O>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@H:3]([N:9]1[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:19][CH3:20])[C:10]1=[O:21])[CH2:2]2
Reactant: COc1cccc2c(=O)n([C@@H]3CN4CCC3CC4)ccc12
Solvent: O
Product: COc1cccc2c1CCN([C@@H]1CN3CCC1CC3)C2=O

Procedure:
Proceeding as in Example 3, but replacing (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-5-ethyl-1(2H)-isoquinolinone with (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-5-methoxy-1(2H)-isoquinolinone, from Example 2, gave (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-3,4-dihydro-5-methoxy-1(2H)-isoquinolinone, m.p. >290° C. [α]D25 -45.7° (c=0.16 H2O).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Br[CH2:12][C:13]#[CH:14].[Cl-].[NH4+]>CN(C=O)C>[CH2:14]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)[C:13]#[CH:12]
Reactant: c1ccc2c(c1)CCNC2
Reactant: C#CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C#CCN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To 1,2,3,4-tetrahydro-isoquinoline (9.4 mmol) in DMF (10 ml), 3-bromo-propyne (4.5 mmol) is added at 0° C. and stirred at room temperature for 18 h. After the reaction mixture is treated with saturated ammonium chloride, the mixture is extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and evaporated down. The crude product is applied to a silica gel column chromatography, which is eluted with following solvents: n-hexane and n-hexane:AcOEt=1:1 (v/v). The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford the title compound. yield 91.2%, Rf=0.67 (n-hexane:AcOEt=1:5).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:10]([F:15])[F:14])[CH:3]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)Oc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of 3-bromophenol (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (1.28 g, 7.39 mmol) in DMF (12.0 mL) was added sodium 2-chloro-2,2-difluoroacetate (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (2.82 g, 18.49 mmol) and Cs2CO3 (4.82 g, 14.79 mmol). The reaction mixture was heated at 100° C. Gas was released from the reaction so care should be taken. After 2 hours, the reaction was cooled to room temperature then diluted with EtOAc, washed with water and then brine and re-extracted three times with EtOAc. The combined organic layers were dried over magnesium sulfate and then filtered, concentrated, and purified with silica gel chromatography (0-5% EtOAc in hexanes) to yield T18.1 as an oil that was used without further purification (yield 61%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[CH3:39][C:40]1[CH:44]=[C:43]([CH2:45][NH2:46])[O:42][N:41]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:46][CH2:45][C:43]1[O:42][N:41]=[C:40]([CH3:39])[CH:44]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: Cc1cc(CN)on1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)on1
Reaction time: 8 h
Yield: 30.9 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 35 mg, 0.081 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.054 mL, 0.487 mmol), (3-methylisoxazol-5-yl)methanamine (16.38 mg, 0.146 mmol), and BOP (64.6 mg, 0.146 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.8 min) to give single enantiomer 2-hydroxy-N-((3-methylisoxazol-5-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (14.1 mg, 0.025 mmol, 30.8% yield): LCMS=526.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.13-8.24 (2 H, m), 7.66-7.78 (4 H, m), 7.53-7.66 (3 H, m), 6.04 (1 H, s), 5.19 (1 H, s), 4.51 (2 H, s), 2.22 (3 H, s); HPLC Peak=9.9 min (Analytical Method A).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15](I)=[CH:16][N:17]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[CH:11][CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([N:43]3[CH2:48][CH2:47][CH:46]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:45][CH2:44]3)[CH:40]=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:37]3[CH:38]=[C:39]([N:43]4[CH2:44][CH2:45][CH:46]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:54])([CH3:53])[CH3:55])[CH2:47][CH2:48]4)[CH:40]=[N:41][CH:42]=3)=[CH:16][N:17]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4c(F)cccc4F)ccc32)cc1
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: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N4CCC(NC(=O)OC(C)(C)C)CC4)c3)c3nc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
A solution of 5-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (92 mg, 0.180 mmol), crude tert-butyl 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidin-4-ylcarbamate (127 mg, 0.316 mmol) and Pd(PPh3)4 (20.83 mg, 0.018 mmol, Strem) in toluene (1 mL) and Ethanol (1.000 mL) was treated with Na2CO3, 2.0 M (0.180 mL, 0.361 mmol). The reaction vessel was capped, degassed and backfilled with argon; and the reaction was heated to 100° C. After 20 h, the solution was cooled to 23° C., diluted with EtOAc (100 mL) and washed with brine (75 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 30-90% EtOAc/hexane), affording tert-butyl 1-(5-(5-(2,6-difluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (85 mg, 71%). MS (ESI, pos. ion) m/z: 660.4 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15]>>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CN(C)CCNc1ccc(N)cn1
Yield: 50.1 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with N1,N1-dimethylethane-1,2-diamine (308 mg, 3.5 mmol) followed by reduction to afford the desired product (280 mg, 50%) as a purple solid: ESI MS m/z 181 [C9H16N4+H]+.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:21]3[O:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:18][C:17]=3[C:16]([O:28][CH3:29])=[CH:15][CH:14]=2)=[O:12])=CC=1)([O-])=O.[NH2:30][C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[C:37]#[N:38]>C(OCC)C>[C:37]([C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[NH:30][C:11]([C:13]1[C:21]2[O:20][C:19]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:18][C:17]=2[C:16]([O:28][CH3:29])=[CH:15][CH:14]=1)=[O:12])#[N:38]
Reactant: Cn1ncc(C#N)c1N
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2oc(N3CCOCC3)nc12
Solvent: CCOCC
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2oc(N3CCOCC3)nc12
Yield: 68.9 %

Procedure:
Starting from 4-methoxy-2-(morpholin-4-yl)-benzooxazole-7-carboxylic acid 4-nitro-phenyl ester (200 mg) and 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (122 mg). Purification by column chromatography on silica eluting with 80% ethyl acetate in heptane followed by 1% methanol in dichloromethane afforded, after trituration with diethyl ether, the title compound as a white solid (132 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.ClCCl.[CH3:25][N:26](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn].C(OCC)(=O)C>[C:25]([C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1)#[N:26]
Reactant: CC(=O)N(C)C
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(Cl)nc1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(C#N)nc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of methyl 3-(6-chloropyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (0.11 g, 0.38 mmol), zinc cyanide (45 mg, 0.38 mmol), zinc (5 mg, 0.08 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (14 mg, 0.019 mmol), and N,N-dimethylacetamide (0.5 mL) was stirred at 120° C. under argon for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (10 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Silica gel flash chromatography (0-100% ethyl acetate in hexanes) gave methyl 3-(6-cyanopyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (70 mg, 0.24 mmol, 63% yield) as a colorless solid. MS found: (M+H)+=295.27.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:16][CH2:15]3)[CH2:11][CH2:10]2)=[CH:3][CH:2]=1>C(O)C.[OH-].[Na+].O>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][C:12]3([CH2:19][CH2:18][CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15]3)[CH2:13][CH2:14]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC1CCC2(CC1)CCN(CCc1ccncc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC1CCC2(CC1)CCN(CCc1ccncc1)CC2
Temperature: 70 °C

Procedure:
To a solution of 0.05 g (0.145 mmol) of the ester from Example 22 in 2 ml ethanol were added three drops of 2N aqueous sodium hydroxide solution. The mixture was heated at 70° C. for 3 h and diluted with 10 ml water. It was washed two times with dichloromethane, and the aqueous layer was adjusted to pH 7-8 with hydrochloric acid. After another extraction with dichloromethane the aqueous layer was concentrated under reduced pressure and the residue stirred with 20 ml of a mixture of ethanol/dichloromethane 9:1. Solids were removed by filtration, and the filtrate was concentrated in vacuo to leave the pure title acid.
Reaction SMILES: [C:1]([C:4](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:5]([NH:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])(=O)[CH3:2].Cl.[C:26]([C:29]1[CH:30]=[NH+:31][CH:32]=[CH:33][CH:34]=1)(=[NH:28])[NH2:27].C([O-])(=O)C.[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:24][C:20]1[CH:19]=[C:18]([C:17]2[C:4]([C:5]([NH:7][CH2:8][CH:9]=[CH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:6])=[C:1]([CH3:2])[N:28]=[C:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[N:27]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: N=C(N)c1ccc[nH+]c1
Reactant: CC(=O)C(=Cc1cccc(Cl)c1)C(=O)NCC=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccnc2)nc(-c2cccc(Cl)c2)c1C(=O)NCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.294 mmol) of 2-acetyl-3-(3-chlorophenyl)-N-(3-phenyl-2-propen-1-yl) acrylamide was dissolved in 5 ml of DMF. 60.1 mg (0.381 mmol) of 3-amidinopyridinium hydrochloride and 28.9 mg of (0.353 mmol) of sodium acetate were added thereto and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was stirred at 120° C. overnight, cooled down at room temperature and purified by the silica gel chromatography (hexane/ethyl acetate=1/2) to obtain the title compound.