Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1ccccc1-c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3OC)c(C(=O)O)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(2-methoxyphenyl)benzoic acid (1.21 g, 2.6769 mmol) was dissolved in a mixed solvent of acetonitrile (30 ml) and water (10 ml), then CAN (3.60 g, 6.6914 mmol) was added thereto at room temperature and the mixture was stirred for 3 hour. The reaction solution was poured into water and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to give the title compound (859 mg, 2.0355 mmol, 76%).
Reaction SMILES: [O:1]([CH:8]([C:10]1[N:15]=[N:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][C:21]1[C:22]([OH:29])=[N:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(OCC)(=O)C.C(N(CC)CC)C>[OH:29][C:22]1[C:21]([CH2:20][NH:19][C:16]([C:13]2[N:14]=[N:15][C:10]([CH:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:9])=[CH:11][CH:12]=2)=[O:18])=[C:26]([CH3:27])[CH:25]=[C:24]([CH3:28])[N:23]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)nn2)c(O)n1
Yield: 79.3 %

Procedure:
A mixture solution of 6-(1-phenoxyethyl)pyridazine-3-carboxylic acid (60 mg, 0.2 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (37 mg, 0.2 mmol), 1-Hydroxybenzotriazole (30 mg, 0.2 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.2 mmol) and triethylamine (0.1 mL) in dichloromethane (50 mL) was stirred at room temperature for 18 hours. The mixture solution was diluting with ethyl acetate (50 mL), washed with water (20 mL). The organic layer was concentrated, the residue was purified by column chromatography (silica-gel, dichloromethane/methanol=30:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-(1-phenoxyethyl)pyridazine-3-carboxamide as a yellow solid (60 mg, 64%). LRMS (M+H+) m/z: calcd 379.17. found 379. HPLC Purity (214 nm): 95%. 1H NMR (300 MHz, CDCl3): δ 9.06 (s, 1H), 8.20 (d, J=9 Hz, 1H), 7.73 (d, J=9 Hz, 1H), 7.15-7.25 (m, 2H), 6.82-6.91 (m, 3H), 5.96 (s, 1H), 5.76-5.78 (m, 1H), 4.63 (d, J=6 Hz, 2H), 2.36 (s, 6H), 1.70 (d, J=6 Hz, 3H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C@H:15]([CH2:16][C:17](=[O:25])[CH:18]=[CH:19]1)[CH2:14][CH2:13]3>C(OCC)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C@H:15]([CH2:16][C:17](=[O:25])[C@@H:18]2[CH2:3][C@@H:19]21)[CH2:14][CH2:13]3
Reactant: C=[N+]=[N-]
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Ethereal diazomethane (40 ml. generated from 3 g. of N-methyl-N'-nitro-N-nitrosoguinidine) is added to a mixture of 17β-methoxy-5α-androst-1-en-3-one (IV, Example 23, 1.0 g.) and palladium diacetate (10 mg.) in diethyl ether (20 ml.). After a few hours the organic diluents are removed by reduced pressure and the residue is column chromatographed thru silica gel (100 g.) eluting by gradient between ethyl acetate:SSB (5:95, 5 l.) and ethyl acetate:SSB (20:80, 5 l.). The appropriate fractions (TLC) are pooled and concentrated to give the title compound, m.p. 114°-118°; MS (m/e) 316, 301, 269, and 243; NMR (CDCl3) 0.77, 0.97, 3.23 and 3.34 δ; CMR (CDCl3) 9.66 δ.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14]C.F[C:26]1[CH:31]=[C:30](F)[CH:29]=[CH:28][C:27]=1[C:33](O)(CN1C=NC=N1)C(F)(F)SCCO.CI.C(Cl)C1C=CC=CC=1>>[CH2:33]([O:24][C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([S:11][CH2:12][CH2:13][OH:14])([F:17])[F:16])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:26]=1
Reactant: OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: COCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CI
Solvent: ClCc1ccccc1
Product: OCCSC(F)(F)C(Cn1cncn1)(OCc1ccccc1)c1ccc(F)cc1F

Procedure:
In a similar manner to Example 1 except that 2-(2,4-difluorophenyl)-1,1-difluoro-1[(2-methoxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol was replaced with 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-hydroxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol and methyl iodide was replaced with benzyl chloride, the experiment was carried out, whereby 2-{[2-(benzyloxy)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propyl]thio}-1-ethanol was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.O.NN.O>C(O)CO>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2-c2ccc(F)cc21
Agent: NN
Solvent: O
Solvent: OCCO
Product: Fc1ccc2c(c1)Cc1ccccc1-2
Temperature: 180 °C

Procedure:
2-Fluoro-9-fluorenone, 20 (1.78 gms, 8.9 mmol) was dissolved in ethylene glycol(60 mL) under a nitrogen atmosphere. Hydrazine hydrate(1.8 mL) was added and the mixture was heated at 180° C. for two hours. The mixture was then cooled and poured into water. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to yield the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.[O:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.[C-:26]#[N:27].[K+]>O>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:22]4([C:26]#[N:27])[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[CH2:14][CH2:13]3)[C:7]=2[CH:18]=1
Reactant: O=C1CCOCC1
Reactant: [C-]#N
Reactant: Cc1ccc2[nH]c(=O)n(C3CCNCC3)c2c1
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1ccc2[nH]c(=O)n(C3CCN(C4(C#N)CCOCC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
6-Methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride salt (D14b, 1 g, 3.74 mmol) was dissolved in water (20 ml) and the pH of the solution was adjusted between 3 and 4. Tetrahydro-4H-pyran-4-one (0.455 g, 4.55 mmol) was added and the mixture stirred at room temperature for 10 minutes, then KCN (0.365 g, 5.61 mmol) was added and the solution was stirred at room temperature for 24 h. A white solid was collected by filtration, washed with cold water and dried in the oven (mixture 9:1 nitrile compound/starting material). This mixture was used without further purification (0.8 g, 2.35 mmol, 63% yield). MH+=341 and 342.
Reaction SMILES: Br[C:2]([CH3:24])([CH3:23])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:18][CH2:17][C:14]([C:19]([O:21][CH3:22])=[O:20])([CH2:15][CH2:16]2)[CH2:13][CH2:12]3)=[CH:7][CH:6]=1)=O.[NH2:25][C:26]1[C:27]([OH:33])=[N:28][CH:29]=[N:30][C:31]=1[NH2:32].Cl>CCO>[NH2:32][C:31]1[C:26]2[N:25]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([C:11]45[CH2:18][CH2:17][C:14]([C:19]([O:21][CH3:22])=[O:20])([CH2:15][CH2:16]4)[CH2:13][CH2:12]5)=[CH:9][CH:10]=3)[C:2]([CH3:23])([CH3:24])[O:33][C:27]=2[N:28]=[CH:29][N:30]=1
Reactant: Nc1ncnc(O)c1N
Reactant: COC(=O)C12CCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Agent: Cl
Solvent: CCO
Product: COC(=O)C12CCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Temperature: 25 °C

Procedure:
To a solution of methyl 4-[4-(2-bromo-2-methylpropanoyl)phenyl]bicyclo[2.2.2]octane-1-carboxylate (Intermediate 26; 507 mg, 1.29 mmol) in abs EtOH (10 mL) was added 5,6-diaminopyrimidin-4-ol (179 mg, 1.42 mmol) followed by 1M HCl (1.4 mL). The suspension was heated under reflux overnight, the reaction mixture was allowed to cool to ambient temperature and then evaporated to dryness. The residue treated with 2M potassium carbonate solution to adjust the pH to 10 and then the mixture was extracted into EtOAc (4×50 mL). The organic extracts were combined, dried (MgSO4) and concentrated to leave the title compound as a yellow gum which was purified on a 12 g Redisep silica cartridge, dry loading the sample on Merck silica (deactivated, ˜1 g) and eluting with DCM-MeOH 0-2%-5% to provide the title compound 150 mg (0.357 mmol, 27%); 1H NMR δ 1.61 (s, 6H), 1.84 (s, 12H), 3.61 (s, 3H), 6.98 (s, 2H), 7.41 (d, 2H), 7.66 (d, 2H), 7.95 (s, 1H); MS m/e MH+ 421.
Reaction SMILES: [O:1]=[C:2]([C:9]#[C:10][Si](C)(C)C)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]>CO.O>[O:1]=[C:2]([C:9]#[CH:10])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: C[Si](C)(C)C#CC(=O)CCCC(=O)O
Solvent: O
Solvent: CO
Product: C#CC(=O)CCCC(=O)O
Temperature: 45 °C
Reaction time: 18 h

Procedure:
The known 5-oxo-7-(trimethylsilyl)hept-6-ynoic acid (1.15 g, 2; prepared using the procedure described in J. Org. Chem., Vol. 62, No. 4, 1997, p. 982-991) was dissolved in methanol (40 ml) and a solution of Borax (Na2B4O7×10H2O, 2.7 g) in water (6 ml) was added. The resulting reaction mixture was stirred for 18 h at 45° C. under argon. The reaction mixture was then quenched by the addition of 1 M HCl (20 ml) and methanol removed in vacuo. The remaining aqueous solution was then extracted with ethyl acetate (4×35 ml). After washing the pooled organic extracts with brine (2×40 ml), drying with MgSO4 and then filtering, volatiles were removed in vacuo. The crude orange oil remaining was purified by flash chromatography (5% ethyl acetate→10%→15% ethyl acetate/hexane) yielding a pale yellow oil product, 5-oxohept-6-ynoic acid (328 mg, 3), which crystallized under storage. 1H NMR (400 MHz, CDCl3): δ1.75 (m, 2H), 2.22 (t, 2H), 2.63 (t, 2H), 4.8 (s, 1H).
Reaction SMILES: [C:1]([O:4]C(=O)C)(=O)[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.[Cl:19][O-].[Ca+2].Cl[O-]>C(O)(=O)C.O.C(O)C>[Cl:19][C:14]1[CH:13]=[C:12]([CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:4])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: [O-]Cl
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(CC(=O)O)cc1Cl
Temperature: 0 °C
Yield: 60.8 %

Procedure:
Acetic anhydride (152 mL, 1.6 moles) was added dropwise to a rapidly stirring mixture of 4-aminophenylacetic acid (195 grams, 1.3 moles) in acetic acid (600 mL) and water (250 mL) at room temperature. After a slight exotherm, the dark brown solution was stirred for one hour at room temperature. The solution was diluted with ethanol (500 mL) and water (250 mL), and a suspension of Calcium hypochlorite (340 grams, 2.3 moles) in water (1 L plus 500 mL rinse) was added portionwise. The temperature rose to 50° C. and the mixture was stirred for 16 hours at room temperature. The mixture was poured into ice-water (8 L) and extracted with ethyl acetate (3×2 L). The combined extracts were washed with saturated brine, dried over magnesium sulfate and concentrated in vacuo to a small volume. Hexane was added and the resulting precipitate filtered, washed with hexane and dried to give the title compound(180 grams) as a brown solid
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16]C)[C:10]([O:14]C)=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:5]=1.B(Br)(Br)[Br:25].CO>C(Cl)Cl>[BrH:25].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([OH:16])[C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH:5]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc2c(c1OC)CC(C1CCCCC1)C=C2CN
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Br
Product: NCC1=CC(C2CCCCC2)Cc2c1ccc(O)c2O
Temperature: -78 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
1-Aminomethyl-3-cyclohexyl-5,6-dimethoxy-3,4-dihydronaphthalene hydrochloride (2.7 g, 8.9 mmol), from Step 2, was dissolved in 72 mL of methylene chloride and cooled to -78° C. Boron tribromide (36 mL of a 1M solution in methylene chloride) was added and the reaction mixture was warmed to 0° C. for 1 h. The reaction mixture was cooled again to -78° C. and 30 mL of methanol was added. After stirring at ambient temperature for 1 h, the reaction mixture was concentrated, diluted with methanol and reconcentrated. The residue was dissolved in methanol and the methanol solution was added dropwise to an excess amount of diethyl ether. The precipitate was filtered and recrystallized from ethanol/ether to give 2.2 g 79% yield) of the title compound, m.p. 212°-213° C.; 1H NMR (d6 -DMSO) δ: 1.0-1.4 (m, 7H), 1.55-1.9 (m, 6H), 2.05-2.15 (m, 1H), 2.47 (dd, 1H), 2.74 (dd, 1H), 5.83 (d, 1H), 6.60 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O>C(#N)C>[CH:5]1[C:6]([C:10]#[N:11])=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3]1[C:2]([NH:1]2)=[C:2]2[NH:1][C:9]3[CH:8]=[CH:7][C:6]([C:10]#[N:11])=[CH:5][C:4]=3[C:3]2=[C:2]2[NH:1][C:9]3[CH:8]=[CH:7][C:6]([C:10]#[N:11])=[CH:5][C:4]=3[C:3]=12
Reactant: N#Cc1ccc2[nH]ccc2c1
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc2[nH]c3c4[nH]c5ccc(C#N)cc5c4c4c5cc(C#N)ccc5[nH]c4c3c2c1
Temperature: 60 °C
Reaction time: 10 h
Yield: 87.2 %

Procedure:
10 ml of acetonitrile was poured into a 200 ml three-neck flask, and 1.42 g of indole-5-carbonitrile was dissolved therein. On the other hand, an oxidant solution was prepared by dissolving 16.2 g of ferric chloride anhydrate and 5.4 g of water in 40 ml of acetonitrile and agitating the resultant mixture for 10 minutes. Then the prepared oxidant solution was dripped into the indole-5-carbonitrile solution for 30 minutes, which was then agitated for 10 hours at the temperature of 60° C. Color of the reaction solution changed from yellow to green with slight heat generation, and the pH was less than 1. After the end of the reaction, the reaction solution was suction-filtered with a perforated funnel, and the filtrate was washed with acetonitrile and then methanol, and then dried to obtain 1.22 g of 6, 11-dihydro-5H-diindolo [2,3-a:2′,3′-c] carbazole-2,9,14-tricarbonitrile (indole-5-carbonitrile trimer) with a green color (yield: 86%). The resultant trimer was pressure-molded with a tablet molding machine and the mold was cut into a piece with the diameter of 10 mm and thickness of 1 mm. A conductivity thereof was measured by the four terminal method and found to be 0.50 S/cm. The result of elemental analysis was: <C9.00H4.03N1.97Cl0.10>3. Further the result of X-ray diffraction crystal analysis indicated that the interlaminar spacing was 0.44 nm.
Reaction SMILES: [CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9](=[O:11])[O-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[I:19].[CH3:20][C:21]([CH3:23])=O>>[I-:19].[CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([O:10][C@@H:21]1[CH:23]2[CH2:13][CH2:12][N+:8]([CH3:9])([CH2:1][CH2:2]2)[CH2:20]1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])N(Cc1ccccc1)c1ccccc1
Reactant: CC(C)=O
Reactant: CI
Product: C[N+]12CCC(CC1)[C@@H](OC(=O)N(Cc1ccccc1)c1ccccc1)C2
Product: [I-]
Temperature: 25 °C

Procedure:
A solution of 300 mg (0.89 mmol) of N-benzyl-N-phenylcarbamate of (R)-3-quinuclidyl (Example 2) and 60 μL of methyl iodide (0.98 mmol) in 9 mL of acetone was refluxed for 2 h. The reaction crude was allowed to cool down at room temperature and the solvent was distilled off under reduced pressure. The obtained solid was broken off with diethyl ether and dried at vacuum at 40° C. to give 480 mg (0.89 mmol) of a hygroscopic white solid corresponding to the title compound. IR (film, cm−1): 1690.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].N([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=C=O>O1CCOCC1>[O:10]=[C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[O:1]1.[CH3:25][CH2:24][CH:23]([C:2]([NH2:3])=[O:1])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCN=C=O
Agent: O=c1[nH]c2ncccc2o1
Solvent: C1COCCO1
Product: CCCCCCCCCC(CC)C(N)=O

Procedure:
100 mg (0.735 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted in analogy to Example 1 with 155.3 mg (0.735 mmol) of 1-isocyanatododecane in dioxane at 80° C. Yield: 33 mg (13%), M+H+: 348.25.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C.O>CCOCC>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([B:23]([OH:24])[OH:22])=[CH:8][CH:9]=1
Reactant: Brc1ccc(-c2ccccn2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: OB(O)c1ccc(-c2ccccn2)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
n-Butyllithium (1.6M in hexane, 2.67 ml) was added to dry ether (16 ml) at -78° C. under argon. A solution of 2-(4-bromophenyl)pyridine (D76, 1.0 g) in dry ether (20 ml) was added dropwise over 5 minutes and allowed to warm to -20° C. for approximately 2 minutes to give a deep red solution. After recooling to -78° C., triisopropylborate (1.18 ml) was added, stirred 30 minutes, warned to ambient temperature to give a yellow cloudy mixture. Water (4.2 ml) and 0.5 MNaOH (4.2 ml) were added with vigorous stirring and the mixture separated. The ether layer was extracted with 0.5M NaOH (2.8 ml) and the combined aqueous extracts were extracted with ether (2×30 ml). The aqueous layer was acidified to pH6 with dilute hydrochloric acid to give the title compound as a beige solid, (0.15 g, 18%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[N:6]=1.Br[C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1>[Pd]>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[N:6]=1
Reactant: Brc1cncnc1
Reactant: Cc1ccc(N)c(C(=O)Nc2csc(C)n2)n1
Agent: [Pd]
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2csc(C)n2)n1

Procedure:
The title compound was prepared from 3-tert-Butoxy-carbonylamino-6-methyl-pyridine-2-carboxylic acid methyl ester in accordance with the general method of example 4; step 2 using 4-amino-2-methylthiazole (CAS: [103392-01-4], European Patent EP 321115) instead of 2-chloro-4-aminopyridine to yield [6-Methyl-2-(2-methyl-thiazol-4-ylcarbamoyl)-pyridin-3-yl]-carbamic acid tert-butyl ester as a light yellow cristalline solid, MS (ISP): m/e=349.0 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-thiazol-4-yl)-amide as a light yellow cristalline solid, MS (ISP): m/e=249.1 (M+H+). Palladium catalysed arylation with 5-bromopyrimidine as described in example 20 yielded the final compound as an off-white crystalline solid, MS (ISP): m/e=327.0 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:10]([C:11]3[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:31][NH2:32]>C(O)C.C(OCC)(=O)C>[CH:19]1([NH:18][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:8][N:7]4[C:2]([NH:31][NH2:32])=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[C:15]([CH3:17])[N:14]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(-c2c(-c3ccc(F)cc3)nn3c(NN)cccc23)nc(NC2CCCC2)n1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
To a solution of 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-methyl-2-pyrimidinamine (100 mg, 0.237 mmol) in ethanol (1 mL) was added hydrazine (500 uL, 15.9 mmol). The reaction mixture was heated in a sealed tube at 90° C. for 72 hours. The mixture was cooled and diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine. The combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (38:2 dichloromethane-methanol) provided N-cyclopentyl-4-[2-(4-fluorophenyl)-7-hydrazinopyrazolo[1,5-α]pyridin-3-yl]-6-methyl-2-pyrimidinamine (45 mg, 46%) as a yellow solid. Rf 0.43 (38:2 CH2Cl2-MeOH); 1H NMR (CDCl3) δ 7.78 (1H), 7.62 (2H), 7.35 (1H), 7.20 (1H), 7.12 (2H), 6.45 (1H), 6.24 (1H), 5.03 (1H), 4.35 (1H), 3.85 (2H), 2.18 (3H), 2.02 (2H), 1.62 (6H); MS m/z 418 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[F:36][C:33]([F:34])([F:35])[C:32]([C:29]1[CH:30]=[N:31][C:26]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[N:27][CH:28]=1)([OH:41])[C:37]([F:40])([F:39])[F:38]
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)c3ccccc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc(-c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)cc1
Temperature: 100 °C
Yield: 71.1 %

Procedure:
A glass microwave reaction vessel was charged with 4,4,5,5-tetramethyl-2-(4-(phenylsulfonyl)phenyl)-1,3,2-dioxaborolane (196 mg, 0.57 mmol, Example 17, Step 2), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (145 mg, 0.52 mmol, Intermediate D), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (24 mg, 0.03 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (0.51 g, 1.56 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (1 mL), and water (0.1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. The reaction was diluted with EtOAc (about 10 mL) and water (about 10 mL). The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of 10% to 20% EtOAc in hexane, to provide 1,1,1,3,3,3-hexafluoro-2-(2-(4-(phenylsulfonyl)phenyl)-5-pyrimidinyl)-2-propanol (171 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.28 (s, 2H), 8.69 (d, J=8.61 Hz, 2H), 8.22 (d, J=8.61 Hz, 2H), 8.04-8.10 (m, 2H), 7.68-7.82 (m, 4H); m/z (ESI, +ve ion) 463.1 (M+H)+. GK-GKRP IC50 (Binding)=0.484 μM. GKRP EC50 (LC MS/MS-2)=0.478 μM.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:9][CH3:10])=[N:5][CH2:6][CH2:7]S)#[N:2].C(NC(NC[CH2:18][SH:19])=N)#N>>[C:1]([NH:3][C:4]([NH:9][CH3:10])=[N:5][CH2:6][CH2:7][CH2:18][SH:19])#[N:2]
Reactant: CNC(=NCCS)NC#N
Reactant: N#CNC(=N)NCCS
Product: CNC(=NCCCS)NC#N

Procedure:
for N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine in the procedure of Example 2(ii) leads to the production of (a)