Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]=2OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([O:25][CH3:26])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]=2[C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([O:25][CH3:26])=[CH:5][CH:4]=1
Reactant: COc1ccc(OC)c2c(OS(=O)(=O)C(F)(F)F)c3ccccc3nc12
Reactant: C#C[Si](C)(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OC)c2c(C#C[Si](C)(C)C)c3ccccc3nc12
Yield: 96.2 %

Procedure:
To a solution of 1,4-dimethoxy-9-trifluoromethylsulfonyloxyacridine (prepared as described in Preparation 1 above) (1.2 g, 3.1 mmol) in dry tetrahydrofuran (10 ml) under N2 were successively added tetrakis(triphenylphosphine) palladium (0), (0.3 g, 0.3 mmol), N,N-diisopropylethylamine (1.6 ml, 9.3 mmol) and trimethylsilylacetylene (1.3 ml, 9.3 mmol). The mixture was stirred at reflux for 5 h. After this time the solvent was evaporated and the residue was dissolved in CH2Cl2 and washed with water. The organic solution was dried an evaporated affording a residue which was purified by column chromatography. Elution with hexane/CH2Cl2 (1:1) gave the title compound (1.0 g, 98%) as a red solid; m.p. 110-111° C. (CH2Cl2). IR (film): ν/cm−1=2810 (w, C≡C), 1608 (s, Ar), 1527 (m, Ar), 1468 (s, Ar); 1H NMR (200 MHz, CDCl3): δH/ppm=0.41 (s, 9H, 3×CH3), 3.99 (s, 3H, OCH3), 4.11 (s, 3H, OCH3), 6.75 (d, J=8.4 Hz, 1H, H-2), 6.93 (d, J=8.4 Hz, 1H, H-3), 7.63 (dd, J=8.0 and 7.2 Hz, 1H, H-7), 7.78 (dd, J=8.4 and 7.2 Hz, 1H, H-6), 8.35 (d, J=8.4 Hz, 1H, H-5), 8.64 (d, J=8.0 Hz, 1H, H-8); 13C NMR (50.3 MHz, CDCl3): δC=0.0 (q, CH3), 55.8 (q, OCH3), 56.1 (q, OCH3), 101.5 (s, ≡C—Si), 103.9 (d, C-2), 105.7 (d, C-3), 111.8 (s, ≡C), 120.5 (s, C-9a), 126.4 (d, C-7), 126.9 (d, C-6), 127.5 (s, C-9), 129.9 (d, C-5), 130.0 (s, C-8a), 130.3 (d, C-8), 142.1 (s, C-4a), 147.0 (s, C-1), 149.4 (s, C-4 and C-10a); MS (EI); m/z (%)=336 [M+1] (10), 335 [M+] (36), 320 (100), 306 (13), 290 (10), 262 (14); HRMS: calcd. for C20H21NO2Si 335.1341; found 335.1336; Elemental analysis: C20H21NO2Si.0.125CH2Cl2 (346.10): calcd. C 69.84, H, 6.19, N, 4.05; found C 69.70, H 6.42, N 4.09.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH:7]=[C:8]4[NH:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:9]4=[CH:10][C:11]=3[C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.C1(P([Pd-4](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)C=CC=CC=1>[CH3:15][C:12]1([CH3:16])[C:11]2[CH:10]=[C:9]3[C:17]4[C:22]([NH:23][C:8]3=[CH:7][C:6]=2[C:5]2[CH:4]=[CH:3][C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][C:13]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=4
Reactant: CC1(C)c2cc(Br)ccc2-c2cc3[nH]c4ccccc4c3cc21
Reactant: OB(O)c1ccccc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC1(C)c2cc(-c3ccccc3)ccc2-c2cc3[nH]c4ccccc4c3cc21

Procedure:
2.47 g (8.1 mmol) of tetrakis(triphenylphosphino)palladium(0) are added to a vigorously stirred suspension of 14.49 g (40 mmol) of 2-bromo-12,12-dimethyl-6,12-dihydro-6-azaindeno[1,2-b]fluorene, 3.69 g (40 mmol) of phenylboronic acid and 63.9 g (127 mmol) of Na2 CO3 in 500 ml of DMF, and the mixture is subsequently heated under reflux for 16 h. After cooling, the precipitated solid is filtered off with suction, washed three times with 50 ml of toluene, three times with 50 ml of ethanol:water (1:1, v:v) and three times with 100 ml of ethanol and recrystallised three times from DMF (about 15 ml/g). Yield: 13 g (36 mmol, 91%).
Reaction SMILES: [F:1][C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C.O>[F:1][C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12](=[N:17][OH:18])[NH2:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: NO
Reactant: N#Cc1ccc(C2(F)CCOCC2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=NO)c1ccc(C2(F)CCOCC2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(4-fluorotetrahydro-2H-pyran-4-yl)benzonitrile (Step 1, 180 mg, 0.877 mmol), hydroxylamine hydrochloride (134 mg, 1.93 mmol) and triethylamine (196 mg, 1.93 mmol) in ethanol (4.5 mL) was stirred and heated at reflux for 4 h. After being cooled to rt, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate. The organic extract was successively washed with brine and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the title compound was obtained (201 mg, 76%): 1H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.70 (d, 2H), 7.44 (d, 2H), 5.81 (s, 2H), 3.88-3.83 (m, 2H), 3.73-3.67 (m, 2H), 2.23-2.06 (m, 2H), 1.87-1.81 (m, 2H); DCI(NH3)-MS m/z 239 (MH)+; HPLC RT (Method I) 3.13 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].CC(C)([O-])C.[K+].[CH:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[C:26]=1[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)=O>C1COCC1>[CH3:1][O:2][C:3]([CH:5]=[CH:18][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[C:26]=1[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:4]
Reactant: Cn1c(-c2cccnc2)c(CCCCCC=O)c2ccccc21
Reactant: COC(=O)CP(=O)(OC)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C=CCCCCCc1c(-c2cccnc2)n(C)c2ccccc12
Reaction time: 0.33 h

Procedure:
Trimethyl phosphonoacetate (328 mg) is added dropwise to a solution of potassium tert-butoxide (220 mg) in THF (5 ml) of 0° under a nitrogen atmosphere. The solution is stirred at 0° for 20 minutes, then cooled to -78°. A solution of 3-(5-formylpentyl)-2-(3-pyridyl)-1-methylindole (450 mg) in THF (5 ml) is added dropwise over 15 minutes. The mixture is kept at -78° for 15 minutes, then the cooling bath is removed. The mixture is stirred overnight at room temperature, then diluted with water (25 ml) and extracted with diethyl ether (3×25 ml). The combined extracts are washed with saturated sodium bicarbonate, then brine, and dried over anhydrous magnesium sulfate. Concentration in vacuo yields the α,β unsaturated ester, 3-(7-methoxycarbonylhept-6-enyl)-2-(3-pyridyl)-1-methylindole.
Reaction SMILES: Cl[C:2]1[N:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7](=[O:16])[CH:8]([CH3:15])[N:9]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]=2[CH:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[N:30]=[CH:29]2.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:15][CH:8]1[C:7](=[O:16])[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]2[CH:23]=[N:24][C:2]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[N:30]=[CH:29]4)=[CH:3][C:4]=2[N:9]1[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CCN1c2cc(Cl)ncc2N(c2ccccc2)C(=O)C1C
Reactant: Nc1ccc2c(cnn2C2CCCCO2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)CCN1c2cc(Nc3ccc4c(cnn4C4CCCCO4)c3)ncc2N(c2ccccc2)C(=O)C1C
Temperature: 95 °C
Yield: 65 %

Procedure:
To a stirred mixture of 7-chloro-2-methyl-1-(3-methylbutyl)-4-phenyl-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one (25.00 mg, 0.073 mmol) and 5-amino-1-(tetrahydropyranyl)-1H-indazole (23 mg, 0.11 mmol) in toluene (2.00 mL) was added bis(dibenzylideneacetone)palladium (10.0 mg, 0.011 mmol), 2,2′-Bis-diphenylphosphanyl-[1,1′]binaphthalenyl (13.5 mg, 0.022 mmol) and Cs2CO3 (71 mg, 0.22 mmol). The resulting mixture was heated at 95° C. for 5 h. LC-MS indicated completion of reaction. The bulk of solvent was removed under reduced pressure to give a crude residue, which was purified by flash column chromatography on silica gel (eluent: 2% methanol in dichloromethane) to give the desired product: (Yield: 65%) MS(ES+): m/z 525.21 [MH+]. HPLC: tR=3.26 (ZQ3, Polar_5 min).
Reaction SMILES: [C:1]([NH:6][CH2:7][C:8]([NH2:10])=O)(=[S:5])[CH2:2][CH2:3][CH3:4].P(Br)(Br)Br>C(OCC)(=O)C>[CH2:2]([C:1]1[S:5][C:8]([NH2:10])=[CH:7][N:6]=1)[CH2:3][CH3:4]
Reactant: CCCC(=S)NCC(N)=O
Agent: BrP(Br)Br
Solvent: CCOC(C)=O
Product: CCCc1ncc(N)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of the product of Example 5C (395 mg, 2.465 mmol) in anhydrous ethyl acetate (12 mL) was treated with phosphorous tribromide (0.189 mL, 1.972 mmol) under a nitrogen atmosphere and stirred at room temperature for 20 minutes. Added additional phosphorous tribromide (0.050 mL) and let stir for 5 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (25 mL). The aqueous wash was extracted with ethyl acetate (2×50 mL), and the organic extracts were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum giving the title compound. Purification by silica gel flash chromatography with 3% methanol/methylene afforded the title product (175 mg, 1.23 mmol, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)[NH2:5].Cl[C:19]1[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]2[S:27][C:28]3[CH2:29][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:32][C:33]=3[C:20]=12>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:19]2[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]3[S:27][C:28]4[CH2:29][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:32][C:33]=4[C:20]=23)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Cl)c23)C1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 54A, the title compound was synthesized from 3-chloro-4-[(3-fluorobenzyl)oxy]aniline from Example 4A (180 mg, 0.72 mmol) and tert-butyl 4-chloro-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate (250 mg, 0.72 mmol) from Example 53A to yield 258 mg (64%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1.[OH-].[K+].Cl>CS(C)=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 0 °C
Yield: 35.6 %

Procedure:
40 ml of dimethyl sulfoxide, 4.2 g of hydroquinone, 5.0 g of 2-chloro-5-trifluoromethylpyridine and 2.3 g of potassium hydroxide were reacted at 150° C. for 2 hours with stirring in a nitrogen atmosphere. After the reaction product was allowed to cool, the product was added to a suitable amount of ice-water, neutralized with 30% concentrated hydrochloric acid, and extracted with methylene chloride. The extract was washed with water and dried over anhydrous sodium sulfate. 2.5 g of 2-(4-hydroxyphenoxy)-5-trifluoromethylpyridine (m.p. 82°-84° C.) was obtained by distilling off the methylene chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C1(C)C=CC=CC=1.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]=[CH:4][C:3]=1[C:20]([C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[F:17])=[O:21]
Reactant: O=C(Cl)c1ccccc1F
Reactant: OB(O)c1ccccc1F
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: [Cs+]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1F)c1ccccc1F
Temperature: 100 °C
Yield: 48.1 %

Procedure:
To a stirred suspension of 2-fluorobenzeneboronic acid (280 mg, 2 mmol), Cs2CO3 (1.63 g, 5 mmol) and tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.02 mmol) in toluene (35 ml) under nitrogen was added dropwise 2-fluorobenzoyl chloride (634 mg, 4 mmol). The suspension was heated at 100° C. for 16 h, cooled to RT and partitioned between ethyl acetate and water. The organic layer was washed with aqueous potassium hydrogencarbonate solution, brine, dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography afforded the title compound (210 mg, 46%). Colorless liquid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]2[CH2:9][O:10][CH2:11][CH:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[C:4]=2O1.[OH-].[NH4+:22]>>[O:1]=[C:2]1[NH:22][C:4]2[CH:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH2:11][O:10][CH2:9][C:5]=2[C:6](=[O:8])[NH:7]1
Reactant: N#Cc1ccc(C2COCc3c2oc(=O)[nH]c3=O)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: N#Cc1ccc(C2COCc3c2[nH]c(=O)[nH]c3=O)cc1

Procedure:
4-(2,4-dioxo-2,3,4,5,7,8-hexahydropyrano[3,4-e][1,3]oxazin-8-yl)benzonitrile (Intermediate AA(3)) was reacted as described in Intermediate X(4) with ammonium hydroxide to give 4-(2,4-dioxo-2,3,4,5,7,8-hexahydro-1H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile (Intermediate AA(4)). LC-MS (M−H)+=270.2.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=1.C([O-])(O)=O.[Na+]>CN(C)C(=O)C>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([O:19][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=4)[CH2:15][CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C([C@H]1CC[C@H](O)CC1)N1CCN(C2CCC2)CC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(O[C@H]2CC[C@H](C(=O)N3CCN(C4CCC4)CC3)CC2)nc1
Reaction time: 0.5 h

Procedure:
To a mixture of 115 mg (0.43 mmol) of trans-(4-Cyclobutyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone (Intermediate 3) in 1 ml of N,N-dimethylacetamide (DMA), 19 mg (0.44 mmol) of sodium hydride was added at room temperature and stirred for 30 min. To the mixture, 100 mg (0.72 mmol) of 6-chloronicotinonitrile (commercially available) was added and stirred at 160° C. for 14 h. The mixture was poured into saturated NaHCO3 solution., extracted with AcOEt. The organic layer was washed with water and brine, dried over MgSO4, and evaporated. The residue was purified by column chromatography on silica eluting with CH2Cl2 and methanol=from 98:2 to 95:5. The combined product fractions were evaporated to dryness to yield 30 mg (11%) of the title compound. MS (m/e): 369.2 (MH+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][CH2:7][CH2:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10].[I-].[Na+].O>CN(C)C=O>[N:1]([CH2:6][CH2:7][CH2:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10])=[N+:2]=[N-:3]
Reactant: O=C(CCCCl)N1CCCc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCC(=O)N1CCCc2ccccc21

Procedure:
Sodium azide (2.2 g), 1-(4-chlorobutanoyl)-1,2,3,4-tetrahydroquinoline, prepared in a manner analogous to that set forth in Preparation 1, (4.2 g) and sodium iodide (1.5 g) were heated in dimethylformamide (25 ml) at 90° for 2 hours. The solution was poured into water and extracted with ethyl acetate. The organic solution was washed, dried and evaporated to give 1-(4-azidobutanoyl)-1,2,3,4-tetrahydroquinoline as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:68])[CH:5]=[CH:6][C@H:7]([CH3:67])[C@H:8]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][CH:60]=1)[C@@H:9]([CH3:56])[CH:10]=[CH:11][C@@H:12]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[CH2:13][C@H:14]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C@H:15]([CH3:39])[CH:16]=[CH:17][CH2:18][O:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:2].[BH4-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][C:4](=[O:68])[CH2:5][CH2:6][C@H:7]([CH3:67])[C@@H:8]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][CH:60]=1)[C@@H:9]([CH3:56])[CH:10]=[CH:11][C@@H:12]([O:48][Si:49]([C:52]([CH3:53])([CH3:54])[CH3:55])([CH3:50])[CH3:51])[CH2:13][C@H:14]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43])[C@H:15]([CH3:39])[CH:16]=[CH:17][CH2:18][O:19][C:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:2]
Reactant: CCOC(=O)C=C[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)C=C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)C=CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CC[C@H](C)[C@@H](OCc1ccc(OC)cc1)[C@@H](C)C=C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)C=CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a stirred solution of unsaturated ester 65 (2.02 g, 2.10 μmol) in MeOH (10 ml), THF (1 ml) at 0° C. was added 0.25 g of NiCl·6H2O then portionwise NaBH4 (0.16 g). After 1 h, the reaction mixture was evaporated and filtered with Celite using Et2O as an eluent (5 ml). The organic phase was concentrated and the residue was purified by flash chromatography (EtOAc/Hexane 1:9) to yield 1.96 g (2.04 μmol) of product 66 (97%) as a colorless oil: IR (CHCl3) 2956, 2929, 2856, 1735, 1613, 1514, 1479, 1448, 1374, 1249, 1174, 1072, 836, 773, 706 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.53 (m, 6H), 7.33 (m, 11H), 6.84 (m, 2H), 5.81 (dd, J=15.7, 6.1 Hz, 1H), 5.65 (m, 1H), 5.45 (m, 2H), 4.65 (m, 1H), 4.56 (d, J=10.9 Hz, 1H), 4.45 (d, J=10.9 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.96 (m, 1H), 3.80 (s, 3H), 3.62 (m, 2H), 3.14 (m, 1H), 2.79 (m, 1H), 2.43 (m, 1H), 2.23 (m, 1H), 1.72 (m, 2H), 1.54 (m, 3H), 1.28 (t, J=7.1 Hz, 3H), 1.06 (d, J=6.7 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H), 0.97 (s, 18H), 0.93 (d, J=6.4 Hz, 3H), 0.17 (s, 3H), 0.154 (s, 3H), 0.151 (s, 3H), 0.14 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.6, 158.8, 144.4, 134.6, 133.6, 132.1, 131.2, 129.1, 128.7, 127.7, 126.8, 126.4, 103.4, 86.6, 86.1, 73.8, 72.8, 66.5, 65.2, 60.0, 55.1, 42.8, 42.3, 35.4, 35.1, 32.3, 29.4, 26.0, 25.9, 18.4, 18.1, 14.6, 14.2, 13.9, −2.9, −4.0, 4.1; HRMS (ESI) calcd for C59H86O7Si2K 1001.5549 (M+K)+, found 1001.5586; [α]20D−9.8 (c 0.95, CHCl3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1
Reactant: Brc1ccccc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(-c2ccccc2Br)cc1
Yield: 86.4 %

Procedure:
Following the general procedure outlined in Synthetic Scheme III, 9.0 g (38 mmol) of 1,2-dibromobenzene was reacted with 3.0 g (19 mmol) of 4-chlorophenylboronic acid (Lancaster). Purification by silica gel chromatography (Waters Prep-500A) with hexane gave 4.39 g (84%) of 1-bromo-2-(4-chlorophenyl)benzene as a colorless oil: NMR (CDCl3) δ 7.18-7.26 (m, 1H), 7.28-7.44 (m, 6H), 7.68 (dd, J=1.5, 8 Hz, 1H).
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O)([CH3:26])=[CH2:25]>C(O)C>[C:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=[N:23][NH:22][C:9]1[CH:8]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:12]2[N:13]=[C:14]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:15]=[C:11]2[N:10]=1)([CH3:26])=[CH2:25]
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccncc3)cc2n1
Reactant: C=C(C)c1cccc(C=O)c1
Solvent: CCO
Product: C=C(C)c1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccncc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
There was dissolved, in ethanol (2 mL), (7-morpholin-4-yl-2-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.4 mg, 0.0976 mM), then 3-isopropenyl-benzaldehyde (14.3 mg, 0.0976 mM) was added to the solution and the mixture was stirred at room temperature overnight. The reaction liquid was filtered and then the resulting solid was washed with diethyl ether to thus give the title compound (26.6 mg, yield: 62%).
Reaction SMILES: [Na].C(O)C.[NH2:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[N:7]=1.[Cl:18][C:19]1[CH:28]=[CH:27][C:22](C=CC#N)=[CH:21][CH:20]=1>ClCCl>[NH2:5][C:6]1[CH2:10][CH:9]([C:22]2[CH:27]=[CH:28][C:19]([Cl:18])=[CH:20][CH:21]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[N:7]=1
Reactant: NC1=NN(c2cccc(Cl)n2)CC1
Reactant: N#CC=Cc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: NC1=NN(c2cccc(Cl)n2)C(c2ccc(Cl)cc2)C1

Procedure:
An 0.3 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 7.2 g. of 2-chloro-6-hydrazinopyridine (Example 2) is added, followed by 8.2 g. of 4-chlorocinnamonitrile. The reaction mixture is refluxed for 18 hours, then is evaporated in vacuo to a gum. Water is added to give a solid. The solid is collected and dissolved in dichloromethane, dried over magnesium sulfate and filtered. The filtrate is concentrated while adding hexane to separate yellow crystals on cooling. The product is collected and washed with ether-hexane to give 10.3 g. of tan solid. The solid is dissolved in dichloromethane, filtered through absorbent magnesium silicate, then is concentrated while adding hexane to give the product of the Example as white crystals, m.p. 157°-158°.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]([C:32](O)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:33])[CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: O=C(O)c1ccccc1-c1cccc(F)c1
Product: O=C(c1ccccc1-c1cccc(F)c1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 3′-fluoro-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C27H23FN4O, 438.51; m/z found, 439.2 [M+H]+.