Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][C:20]=1[N+:31]([O-:33])=[O:32].C(N(CC)CC)C>CN(C)C=O>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][C:20]=3[N+:31]([O-:33])=[O:32])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)ccc1Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3ccc(-c4ccccc4)cc3[N+](=O)[O-])cc12
Temperature: 110 °C
Yield: 24 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 4-bromo-3-nitrobiphenyl were used. Triethylamine was used as base, N,N-dimethylformamide was used as solvent, and the reaction was heated at 110° C. for 12 hours. Column chromatography afforded the title compound (24%) as a red amorphous solid: 1H NMR (CDCl3) δ 9.63 (br s, NH), 8.97 (br s, NH), 8.42 (d, J=2.2 Hz, 1 H), 7.56-7.25 (m, 9H), 7.08 (d, J=9.0 Hz, 2H), 3.50-3.32 (m, 2H), 2.95-2.79 (m, 2H), 2.59-2.52 (m, 1H), 2.53 (s, 3H), 2.05-1.71 (m, 4H); 13C NMR (CDCl3) δ 144.4, 138.8, 134.9, 134.5, 132.4, 131.1, 130.2, 129.7, 129.0, 127.3, 126.2, 124.7, 124.1, 120.8, 116.7, 115.9, 112.7, 112.0, 67.9, 57.4, 40.6, 31.2, 28.6, 21.9; FAB HRMS calculated for [C26H26N4O2.H]427.2136, found 427.2099.
Reaction SMILES: [H-].[Na+].[C:3](=[N:7][OH:8])([NH2:6])[CH2:4][CH3:5].[C:9]1([C:15]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:16]2[CH2:21][CH:20]([C:22](OC)=O)[CH2:19][N:18]=[CH:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[C:32]1([C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:16]2[CH2:21][CH:20]([C:22]3[O:8][N:7]=[C:3]([CH2:4][CH3:5])[N:6]=3)[CH2:19][N:18]=[CH:17]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCC(N)=NO
Reactant: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1noc(C2CN=CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
Prepared by a procedure similar to Example 9, where sodium hydride (60% dispersion in mineral oil 56 mg, 1.4 mmol) and propionamidoxime (123 mg, 1.4 mmol) were suspended in dry THF in an oven dried round bottom flask with stirring under nitrogen at 0° C. After 15 minutes stirring the ice bath was removed and the grey suspension refluxed 45 minutes to give a white suspension. 1-Triphenylmethyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (540 mg, 1.4 mmol) was added, dissolved in dry THF and reflux continued 18 hours. The solvents were evaporated in vacno and the residue was chromatographed (silica, chloroform/methanol 9:1) to yield 1-triphenylmethyl-1,4,5,6-tetrahydro-5-(3-ethyl-1,2,4-oxadiazol-5-yl)pyrimidine 420 mg (70%). This product was dissolved in triflouroacetic acid (2 mL), with stirring at room temperature for 24 hours. The yellow solution was then evaporated in vacuo, and the residue recrystallized from methanol/ether to yield 144 mg (49%) white crystals, mp 116°-118° C. identified by 300 MHz nmr.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([O:20]C)=O)[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.[NH3:22]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([NH2:22])=[O:20])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1
Reactant: N
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CC1(C)OB(c2ccc(CC(N)=O)cc2F)OC1(C)C
Yield: 84.1 %

Procedure:
A solution of methyl 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (0.1 g, 0.340 mmol) in ammonia (MeOH, 10 mL, 160 mmol) was stirred at 20° C. for 16 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo to yield 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (100 mg, 0.286 mmol, 84.0% yield): 1H NMR (400 MHz, DMSO-d6) δ 7.56 (t, J=7.2 Hz, 1H), 7.14-6.98 (m, 2H), 3.59 (s, 2H), 1.26 (s, 12H); ES-LCMS m/z 280.1 (M+H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]#[C:36][CH3:37])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]#[C:36][CH3:37])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCN)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 0.300 g (0.564 mmol) of methyl (2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)({[4-(2-butynyloxy)phenyl]sulfonyl}amino)ethanoate (from Example 199) in 1.5 mL of dichloromethane was added 1.5 mL of trifluoroacetic acid and the resulting mixture was stirred for 2 h at room temperature and then concentrated in vacuo. The residue was diluted with ethyl acetate and the organics were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to provide 0.244 g of methyl(2R)-[4-(2-aminoethoxy)phenyl]({[4-(2-butynyloxy)phenyl]sulfonyl}amino)ethanoate pure enough for use in the next step. Electrospray Mass Spec 433.3 (M+H)+
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:18]=[CH:17][C:9]([C:10]([O:12]CC3CC3)=[O:11])=[CH:8][C:7]=2[C:19]([F:22])([F:21])[F:20])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO>[CH:1]1([CH2:4][O:5][C:6]2[CH:18]=[CH:17][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=2[C:19]([F:20])([F:21])[F:22])[CH2:3][CH2:2]1
Reactant: O=C(OCC1CC1)c1ccc(OCC2CC2)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCC2CC2)c(C(F)(F)F)c1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a solution of cyclopropylmethyl 4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzoate (0.642 g, 2.043 mmol) in THF:MeOH (1:1, 10 mL) was added LiOH (1M, aq) (12.26 mmol). The reaction was stirred overnight, quenched with HCl (1M, aq) and extracted with EtOAc (twice). The combined extracts were dried over MgSO4 and concentrated to give the title compound as a white solid (0.502 g). LCMS m/z=261.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 0.39-0.46 (m, 2H), 0.62-0.71 (m, 2H), 1.23-1.38 (m, 1H), 4.03 (d, J=6.57 Hz, 2H), 7.02 (d, J=8.72 Hz, 1H), 8.23 (dd, J=8.72, 2.15 Hz, 1H), 8.34 (d, J=2.02 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[C:26]([Cl:36])[C:23]=1[CH:24]=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]4[N:19]=[C:24]([C:23]5[C:22]([Cl:21])=[CH:29][C:28]([N:30]6[CH2:31][CH2:32][O:33][CH2:34][CH2:35]6)=[CH:27][C:26]=5[Cl:36])[NH:20][C:15]=4[CH:14]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1N
Reactant: O=Cc1c(Cl)cc(N2CCOCC2)cc1Cl
Solvent: CS(C)=O
Product: Clc1ccc(-c2nnc(-c3ccc4nc(-c5c(Cl)cc(N6CCOCC6)cc5Cl)[nH]c4c3)o2)cc1
Reaction time: 18 h

Procedure:
To a 50 ml rbf was added 0.2250 g (0.785 mmol) 4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]benzene-1,2-diamine, 0.2041 g (0.785 mmol) of 2,6-Dichloro-4-morpholin-4-yl-benzaldehyde, and 5 mL of DMSO. To this dark brown solution was added 0.0190 g (0.118 mmol) of FeCl3. It was allowed to stir open to air for 18 h. The crude was then extracted with EtOAc, and the combined extracts were washed with water, brine and dried with Na2SO4. The volatiles were removed in vacuo and the concentrate was purified on silica gel (ACN/DCM, 1:9 to 10:0) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.30 (d, J=5.05 Hz, 4 H) 3.71-3.77 (m, 4 H) 7.17 (s, 2 H) 7.70-7.75 (m, 2 H) 7.90 (d, J=8.72 Hz, 1 H) 7.99-8.07 (m, 1 H) 8.19 (d, J=8.21 Hz, 2 H) 8.27 (br. s., 1 H) 8.47 (s, 1 H) 13.17 (d, J=8.97 Hz, 1H. MS (m/z) 528.0 M (+1), tR=1.41, Meth 10
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH:6][NH2:7])=[NH:5].C[O-].[Na+].CC[O:13][C:14]([CH:16]([C:18]([CH3:20])=O)[CH3:17])=O>C(O)C>[NH2:2][N:3]1[C:14](=[O:13])[C:16]([CH3:17])=[C:18]([CH3:20])[N:5]=[C:4]1[NH:6][NH2:7]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: N=C(NN)NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(NN)n(N)c(=O)c1C
Yield: 53.3 %

Procedure:
A mixture of 13.22 g of diaminoguanidine hydrochloride, 5.4 g of sodium methoxide, 7.2 g of ethyl-2-methyl acetoacetate and 100 ml of ethanol was reacted as described in Example 1, giving 4.5 g of 3-amino-2-hydrazino-5,6-dimethyl-4(3H)-pyrimidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Cl)nc1

Procedure:
A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g (0.15 mol) ethanol, 22.7 g (0.11 mol) dicyclohexylcarbodiimide and 3.7 g (0.03 mol) dimethylaminopyridine in 200 ml methylene chloride was heated at reflux for 2 hours. The mixture was allowed to cool, solvent removed in vacuo and residue subjected to flash chromatography to give the title compound as a low-melting white solid. PMR (CDCl3): δ1.44 (3H, t, J~6.2 Hz) 4.44 (2H, q, J- 6.2 Hz), 7.44 (1H, d, J~8.1 Hz), 8.27 (1H, dd, J~8.1 Hz, 3 Hz), 9.02 (1H, d, J3 Hz).
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:38](Cl)([Cl:40])=[O:39]>C1(C)C=CC=CC=1>[CH2:20]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:38]([Cl:40])=[O:39])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)Cl
Temperature: 100 °C

Procedure:
Distearyl carbamoyl chloride was prepared by charging 2.1 kg of toluene into a flask and then simultaneously adding 1.8kg of melted distearyl amine and 0.5 kg of phosgene under agitation at 55°-60°C. The temperature was then raised to 100°C. The reaction was carried out under slight vacuum and reflux. When the conversion was almost 100%, corresponding to a yield of about 1.8 kg distearyl carbamoyl chloride, toluene and phosgene were evaporated.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[C:6](Cl)(=[O:10])[C:7](Cl)=[O:8]>O1CCCC1.O>[CH3:1][N:2]1[C:7](=[O:8])[C:6](=[O:10])[NH:5][C:3]1=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNC(N)=O
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)NC(=O)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To an ice-cold solution of 1-methylurea (200 mg, 2.70 mmol) in dry tetrahydrofuran (6 mL) was added oxalyl chloride (0.26 mL, 2.97 mmol) dropwise, under a nitrogen atmosphere. The reaction mixture was stirred at 0-5° for 2 h and then allowed to warm to room temperature for 1 h before being diluted with water. The product was extracted with ethyl acetate, and the extracts were washed with water, dried and evaporated to give the product as an off-white solid (326 mg, 94%), mp 146-149° C. (lit. 145-148° C.).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)[CH2:4][C:5](=[O:13])[CH2:6][C:7]([C:9]([F:12])([F:11])[F:10])=O.[OH-].[NH4+:18]>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:18]=1
Reactant: O=C(CC(=O)C(F)(F)F)CC(=O)C(F)(F)F
Reactant: [NH4+]
Agent: [OH-]
Product: Oc1cc(C(F)(F)F)nc(C(F)(F)F)c1
Temperature: 130 °C

Procedure:
A mixture of 30 g 1,5-di(trifluoromethyl)-1,3,5-trioxopentane and 125 ml 28% aqueous ammonium hydroxide was heated in an autoclave at 130° C. for 5 hours. The reaction mixture was concentrated in vacuo, dissolved in 350 ml ethanol and treated with 11 ml 6N hydrochloric acid. The resulting mixture was concentrated in vacuo, 100 ml water added to the residue and filtered to give 8.0 g 2,6-di(trifluoromethyl)-4-hydroxypyridine, m.p. 123°-130° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:25][S:26]([NH:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][C:5]=2[O:4][CH:3]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1cc2occ(NS(C)(=O)=O)c(=O)c2cc1Oc1ccccc1

Procedure:
3-Amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with methanesulfonyl chloride to obtain 3,7-bis(methylsulfonylamino)-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: Cl.[F:2][C:3]1([F:10])[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.[C:11](Cl)(=[O:18])[O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15].C(N(CC)CC)C>ClCCl>[F:2][C:3]1([F:10])[CH2:8][CH2:7][CH:6]([NH:9][C:11](=[O:18])[O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])[CH2:5][CH2:4]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: NC1CCC(F)(F)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCC(F)(F)CC1)OCC(Cl)(Cl)Cl

Procedure:
4,4-difluorocyclohexylamine hydrochloride (8) is acylated with 2,2,2-trichloroethyl carbonochloridate (9) using an organic base such as triethylamine in an inert solvent such as dichloromethane to give 2,2,2-trichloroethyl 4,4-difluorocyclohexylcarbamate, (7), Step 1.
Reaction SMILES: [F:1][C:2]([F:30])([CH:8](OC(C(C1NC=CN=1)=O)=S)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:1][C:2]([F:30])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCCCCCCCCCC(OC(=S)C(=O)c1ncc[nH]1)C(F)(F)C(=O)OCC
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCC(F)(F)C(=O)OCC
Yield: 77.5 %

Procedure:
Ethyl bromodifluoroacetate (6.0 g) and dodecyl aldehyde (1.84 g) were mixed with anhydrous tetrahydrofuran (40 ml ) under argon atmosphere, and the solution was added dropwise to a suspension of zinc powder (2.2 g) and copper bromide (I) (0.22 g) in anhydrous tetrahydrofuran (40 ml ) which was heated to a refluxing temperature. The mixture, after heating under reflux for 5 hours, was cooled and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 20:1 to 10:1) to give ethyl 2,2-difluoro-3-hydroxytetradecanoate (0.92 g). After the mixture of ethyl 2 , 2-difluoro-3-hydroxytetradecanoate (0.92 g) and 1,1'-thiocarbonyl imidazole (1.26 g) in 1,2-dichloroethane was heated under reflux for 1 hour, it was cooled and concentrated. The residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 30:1 to 10:1 ) to give ethyl 2,2-difluoro-3-imidazoylthiocarbonyloxytetradecanoate (1.32 g). To a solution of ethyl 2 , 2-difluoro-3-imidazoylthiocarbonyloxytetradecanoate (1.32 g) dissolved in toluene (40 ml ) under argon atmosphere, which was heated under reflux, was added dropwise a solution of tri-n-butyltin hydride (2.93 ml ) in toluene (70 ml ). The mixture, after heating under reflux for 2 hours, was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 300:1 to 50:1 ) to give ethyl 2,2-difluorotetradecanoate (0.67 g). To a solution of ethyl 2,2-difluorotetradecanoate (489 mg) in N,N-dimethylformamide (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (300 mg) and triethylamine (1.5 ml). The mixture was stirred for 12 hours. After the solvent was evaporated, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol-water (from 8.5:1:0.05 to 7:1:0.05) to give SPK182 in the yield of 95 mg.
Reaction SMILES: [H][H].[CH2:3]=[C:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14]>C1(C)C=CC=CC=1.[Pd]>[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:14]
Reactant: C=C1CCc2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Cc1ccc2ccccc2c1O
Temperature: 110 °C
Yield: 98.4 %

Procedure:
A 50-ml reaction vessel was charged with 20 ml of toluene and 100 mg of 5% Pd/C (dry type) and hydrogen gas was passed through the mixture at room temperature. After conducting activation for 1 hour, the atmosphere in the vessel was replaced with nitrogen and the vessel was heated to 110° C. To the mixture a solution of 1.25 g (7.9 mmoles) of 2-methylene-1-tetralone in 20 ml of toluene was added dropwise over 2 hours. After the addition, refluxing state was maintained for further 1 hour to permit the reaction to proceed until completion. GLC analysis revealed that there was formed 1.23 g of 2-methyl-1-naphthol (conversion: 98.5%; selectivity: 100%).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[CH:16][C:15]=2[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]#[N:37]>CC(C)=O>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:35][C:36]#[N:37])=[CH:25][CH:26]=3)=[CH:16][C:15]=2[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: Oc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(9-benzyl-6,7,8,9-tetrahydro-5H-carbazol-3-yl)-phenol (0.421 g, 1.191 mmol) was reacted with K2CO3 (0.198 g, 1.429 mmol) and bromoacetonitrile (0.171 g, 1.429 mmol) in acetone to give the product (0.369 g, 0.940 mmol, 79%) as a white solid, mp 149-153° C. 1H NMR (DMSO-d6) δ 1.79-1.86 (m, 4H), 2.63-2.72 (m, 4H), 5.19 (s, 2H), 5.34 (s, 2H), 7.04 (d, J=7.5 Hz, 2H), 7.12 (d, J=7.5 Hz, 2H), 7.22 (t, J=7.2 Hz, 1H), 7.27-7.30 (m, 3H), 7.41 (d, J=8.6 Hz, 1H), 7.62 (s, 1H), 7.65 (d, J=8.6 Hz, 2H); [ESI(+)], m/z 393 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:39]1[CH:43]=[C:42]([CH2:44][OH:45])[NH:41][N:40]=1)CCC>O1CCOCC1.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>[OH:45][CH2:44][C:42]1[NH:41][N:40]=[C:39]([C:2]2[N:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]3[C:10]([C:11](=[O:31])[C:12]([N:14]4[CH2:19][CH2:18][N:17]([C:20]5[N:24]([C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[N:23]=[N:22][N:21]=5)[CH2:16][CH2:15]4)=[O:13])=[CH:9][NH:8][C:7]=23)[CH:43]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(CO)[nH]n1
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COc1cnc(-c2cc(CO)[nH]n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Temperature: 120 °C
Yield: 21.8 %

Procedure:
In a sealable, flask a mixture of 1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.150 g, 0.321 mmol) in 1,4-dioxane (5 mL) was prepared. (3-(tributylstannyl)-1H-pyrazol-5-yl)methanol (0.137 g, 0.353 mmol) was added followed by tetrakis(triphenylphosphine)palladium (0) (0.150 g, 0.130 mmol). The mixture was flushed with N2, and flask was sealed. The mixture was then heated to 120° C. for 14 h. After cooling to rt, the mixture was diluted with DMF, and filtered through a plug of celite to remove any solids. The liquid was concentrated under reduced pressure, and the residue was dissolved in DMF. The DMF solution was purified by prep HPLC to give 0.037 g of an off-white solid as the 1-(7-(5-(hydroxymethyl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione. LCMS: m/e 529.2 (M+H)+, ret time 1.78 min (method 2). 1H NMR (500 MHz, MeOD) δ ppm 8.65 (s, 1 H) 7.98 (s, 1 H) 7.56-7.80 (m, 5 H) 7.16 (s, 1 H) 4.81 (s, 2 H) 4.15 (s, 3 H) 3.83-3.87 (m, 2 H) 3.63-3.68 (m, 2 H) 3.40-3.44 (m, 2 H) 3.34-3.39 (m, 2 H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[N:32]=1>CN(C=O)C.C(Cl)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>[Cl:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([NH:16][CH:17]([CH3:18])[CH3:19])=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:3]=2)[N:32]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccc(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(Cl)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 100 °C
Yield: 56.5 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (1.00 g, 1.914 mmol) and 4-chloro-2-(tributylstannyl)pyrimidine (0.966 g, 2.393 mmol) in DMF (5 mL) followed by Pd(PPh3)4 (0.111 g, 0.096 mmol, Strem) and Cut (0.072 g, 0.383 mmol, Aldrich). The reaction was stirred and heated in a Initiator microwave reactor at 100° C. for 1 h. The mixture was then diluted with DCM and washed with H2O, brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified with flash chromatography (eluent: 25%-60% EtOAc in Hexanes) to give 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (550 mg, 1.081 mmol, 56.4%) as a green solid. MS (ESI, pos. ion) m/z: 508.9 (M+1).