Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl-].[F:9][C:10]1[C:15]([N:16]([CH3:36])[C:17]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])[C:20]=2[C:32]([F:35])([F:34])[F:33])=[O:18])=[CH:14][CH:13]=[C:12]([F:37])[C:11]=1[CH2:38][NH3+:39].N1C=CC=CC=1>C1COCC1>[C:1]([NH:39][CH2:38][C:11]1[C:10]([F:9])=[C:15]([N:16]([CH3:36])[C:17]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([F:31])([F:30])[C:26]([F:29])([F:27])[F:28])[C:20]=2[C:32]([F:33])([F:34])[F:35])=[O:18])[CH:14]=[CH:13][C:12]=1[F:37])(=[O:3])[CH3:2]
Reactant: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn1C)c1ccc(F)c(C[NH3+])c1F
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NCc1c(F)ccc(N(C)C(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)c1F
Reaction time: 20 h
Yield: 99.1 %

Procedure:
Acetic anhydride (34 mg, 0.34 mmol, 1.3 eq) in THF (1 ml) was added to a solution of [2,6-difluoro-3-(methyl{[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)phenyl]methanaminium chloride (130 mg, 0.26 mmol) and pyridine (43 mg, 0.54 mmol, 2.1 eq.) in THF (2.5 ml), and the mixture was left at room temperature for 20 h. After concentration under reduced pressure, the product was purified by column chromatography (hexane/ethyl acetate) to give N-[3-(acetamidomethyl)-2,4-difluorophenyl]-N,1-dimethyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (131 mg, 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([C:26](=[O:31])N(OC)C)[CH:23]=[CH:22][N:21]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:40][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([C:26](=[O:31])[CH3:40])[CH:23]=[CH:22][N:21]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CON(C)C(=O)c1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of (1-{4-[7-(methoxy-methyl-carbamoyl)-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester [prepared in a manner analogous to that described in Int-24-0] (250 mg, 0.48 mmol) in THF (10 mL) under an atmosphere of argon at 0° C. was added a 3 M solution of methyl-magnesium chloride in THF (0.4 mL, 1.2 mmol, 2.5 equiv). The resulting was stirred for 1 h at 0° C., then for 5 h at room temperature. The resulting material was added to a saturated aqueous NH4Cl solution (10 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic phases were dried (Na2SO4 anh) and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 25 g SNAP cartridge: 100% hexane for 1 min., gradient to 75% hexane/25% EtOAc over 1 min., 75% hexane/25% EtOAc for 3 min., gradient to 50% hexane/50% EtOAc over 1 min., 50% hexane/50% EtOAc for 4.5 min, gradient to 25% hexane/75% EtOAc over 2.5 min., gradient to 100% EtOAc over 2 min., 100% EtOAc for 10.6 min.) to give {1-[4-(7-acetyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (151 mg, 66%):
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[C:5]2[O:6][C@@H:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]3[C:4]=2[CH:3]=1>[OH-].[Na+].O1CCOCC1.O>[Cl:1][C:2]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:5]2[O:6][C@@H:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]3[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc(Cl)cc2c1O[C@@H]1CCCC[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)cc2c1O[C@@H]1CCCC[C@H]21
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of 2 g methyl 2-chloro-cis-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate in 30 ml 1N sodium hydroxide and 5 ml dioxane is stirred at 60° C. for 5 hours. This is then diluted with water, filtered, acidified with acetic acid, extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness to obtain an oily product which crystallizes on standing. This is recrystallyzed to obtain 2-chloro-cis-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid. (M.P. 132°-4° C.)
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O>[CH:21]1([C:2]2[C:3]3[N:4]([CH:18]=[CH:19][N:20]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:7]=2)[CH2:23][CH2:22]1
Reactant: OB(O)C1CC1
Reactant: FC(F)(F)c1ccc(-c2cc(Br)c3nccn3c2)cc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(C3CC3)c3nccn3c2)cc1
Yield: 66.5 %

Procedure:
To a Schlenk flask was added 8-bromo-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.25 step 3) (3.026 g, 8.9 mmol), cyclopropyl boronic acid (103 mg, 13 mmol), tri(cyclohexyl)phosphine (101 mg, 4 mol %), potassium phosphate (6.53 g, 31 mmol), 50 mL of toluene and 2.5 mL of water. The reaction mixture was degassed under Ar for 5 min, then palladium acetate (41 mg, 2 mol %) was added and continued to bubble in Ar, then placed into a 100° C. oil bath for 23 h. The cooled reaction mixture was decanted and filtered through a pad of celite/Si Gel, washed aqueous material with EtOAc and combined organic layers were concentrated to give a green-colored mixture. This residue was purified by silica gel column chromatography with heptane/EtOAc followed by trituration with heptane and very little ether to give the title compound as a green solid (1.79 g, 67%). MS (ISP) 303.1 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1([C:18]2[C:27]([CH3:28])=[CH:26][C:25]3[C:24]([CH3:30])([CH3:29])[CH2:23][CH2:22][C:21]([CH3:32])([CH3:31])[C:20]=3[CH:19]=2)[C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]([O:15]CC)=[O:14])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.O.[OH-].[Na+].Cl>C1COCC1.CCOC(C)=O.O>[CH3:1][C:2]1([C:18]2[C:27]([CH3:28])=[CH:26][C:25]3[C:24]([CH3:30])([CH3:29])[CH2:23][CH2:22][C:21]([CH3:32])([CH3:31])[C:20]=3[CH:19]=2)[C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CCOC(=O)C=Cc1ccc2c(c1)C(C)(c1cc3c(cc1C)C(C)(C)CCC3(C)C)CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2c(cc1C1(C)COc3ccc(C=CC(=O)O)cc31)C(C)(C)CCC2(C)C

Procedure:
A solution of ethyl 3-[3-methyl-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3-dihydrobenzofuran-5-yl]acrylate (320 mg, 0.74 mmol), water (40 μl) and sodium hydroxide (240 mg, 6 mmol) in THF is heated to reflux for 24 h. The reaction mixture is poured onto an AcOEt/water mixture, acidified to pH=1 with a concentrated hydrochloric acid solution, and extracted once with ethyl acetate. After separation the organic phase is washed twice with water, dried over magnesium sulphate and concentrated in vacuo at 40° C. in a rotary evaporator. The solid obtained is crystallized in heptane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][C:16](Br)=[C:17]([Br:20])[C:18]=2[CH3:19])[N:11]([CH3:22])[N:10]=1.C(O)(=O)C.O>[Zn].CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][CH:16]=[C:17]([Br:20])[C:18]=2[CH3:19])[N:11]([CH3:22])[N:10]=1
Reactant: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)sc(Br)c1Br
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1c(Br)csc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Into 250-mL three-necked round bottom flask equipped with a mechanical stirrer and condenser under an atmosphere of nitrogen was added 19.26 g of 3-(2-chloro-6-fluorophenyl)-1-methyl-5-(4,5-dibromo-3-methyl-2-thienyl)-1H-1,2,4-triazole, 72 mL of acetic acid, 16 mL of water, and 3.25 g of zinc dust. The temperature of the reaction mixture was heated to 100° C. and was maintained at that temperature. After three hours the mixture was allowed to cool to room temperature and was poured into ether (500 mL) and washed with water (2×150 mL), saturated sodium bicarbonate (3×150 mL), brine, dried (Na2SO4) and the solvent removed in vacuo to give 15.4 g (96.4% yield) of the title compound as a white solid: mp 120-121° C; 1H NMR (CDCl3) δ 7.5 (s, b, 1H), 7.3-7.4 (m, 2H), 7.1 (m, 1H), 4.0 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21](O)[C:20]=2[N:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[N:16]1[C:25]2[C:20](=[C:21]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1cccc2nccnc12
Solvent: c1ccncc1
Product: O=S(=O)(Oc1cccc2nccnc12)C(F)(F)F
Temperature: 25 °C
Yield: 85.1 %

Procedure:
Add trifluoromethanesulfonic anhydride (0.66 mL, 3.94 mmol) to a solution of quinoxalin-5-ol (Yamamoto, T. et al., J. Am. Chem. Soc. 1996, 118, 3930-3936; 500 mg, 3.42 mmol) in pyridine (6.8 mL) at 0° C. Allow the reaction to warm slowly to room temperature over 18 h. Add saturated aqueous sodium bicarbonate solution (100 mL) and extract the mixture with methylene chloride (3×100 mL). Dry the combined organic solutions with sodium sulfate, concentrate in vacuo, and purify by flash column chromatography to provide the subtitled compound (810 mg, 85%) as an off-white solid. MS ESI+ m/e 279 (M+1). 1H NMR (CDCl3): δ 8.85 (m, 2H), 8.18 (m, 1H), 7.84 (m, 1H), 7.63 (m, 1H). TLC (SiO2): Rf0.2 (3:1 hexanes/ethyl acetate).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27]Br.Cl.[CH3:30][CH2:31][CH2:32]CCC>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:24]2[CH2:32][CH2:31][CH2:30][CH2:27][CH2:26][CH2:25]2)[C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: BrCCCCBr
Reactant: N#Cc1ccc(NC(=O)Nc2cccc(C#N)c2)cc1
Reactant: CCCCCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC(=O)N(c2cccc(C#N)c2)C2CCCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
N-(3-Cyanophenyl)-N'-(4-cyanophenyl)urea (0.25 g, 0.95 mmol) was dissolved in DMF (2 ml) and added to a cooled slurry of sodium hydride (0.80 g, 2.0 mmol, hexane washed to remove the mineral oil) in dimethylformamide (25 ml) under a nitrogen atmosphere. After strirring for 15 min, 1,4-dibromobutane (0.25 g, 0.95 mmol) was added slowly. The reaction was stirred at 0° C. for 1 h and then allowed to warm to 75° C. for 3 h. To the reaction additional sodium hydride was added and the reaction was heated to 75° C. for an additional 6 h. The reaction was allowed to cool to ambient temperature, was poured into 1N HCl and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried (MgSO4) and concentrated to give a viscous oil. The oil was purified by flash chromatography on silica gel eluting with methylene chloride: ethyl acetate 95:5 to give N-(3-cyanophenyl)-N'-(4-cyanophenyl)cycloheptylurea as an oil (0.075 gm 0.24 mmol); LRMS (M+H)+ m/z 317; 1H NMR (CDCl3): 7.7-7.45(m, 6H), 7.4(d, 2H), 3.82(m, 4H), 1.95(m, 4H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[C:17]1[NH:18][CH:19]=[CH:20][CH:21]=1)=[O:6].[CH3:25][O:26]C1C=CC(C(Cl)=O)=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:25][O:26][C:24]1[CH:23]=[CH:22][C:4]([C:5]([NH:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[C:11]3[C:17]2[NH:18][CH:19]=[CH:20][CH:21]=2)=[O:6])=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C(Nc1ccc2[nH]nc(-c3ccc[nH]3)c2c1)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccc[nH]4)c3c2)cc1
Yield: 102.9 %

Procedure:
2,2-Dimethyl-propionic acid 5-amino-3-(1H-pyrrol-2-yl)-indazol-1-yl ester (0.38 mmol) (from Example 25) was coupled with 4-methoxy-benzoyl chloride (0.4 mmol) and triethylamine in DCM at 0° C. to give 130 mg of the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9]O)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].P(Br)(Br)[Br:12]>C1COCC1>[Br:12][CH2:9][C:3]1[C:2]([F:1])=[C:7]([CH3:8])[CH:6]=[CH:5][N:4]=1
Reactant: Cc1ccnc(CO)c1F
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: Cc1ccnc(CBr)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
Intermediate 6 ((3-fluoro-4-methyl-2-pyridinyl)methanol, 246 mg, 1.743 mmol) was dissolved in 10 mL of anhydrous THF. Phosphorous tribromide (ALDRICH, 519 mg, 1.917 mmol) was added. Reaction mixture was stirred at room temperature overnight. Solvent was evaporated and residue was partitioned between Et2O and NaHCO3 (aqueous saturated solution). Organic layer was dried over MgSO4 (anh), filtered and concentrated to give the title compound (372 mg, quantitative yield). 1H NMR (300 MHz, DMSO-d6) ppm: 8.23-8.24 (m, 1H), 7.34-7.37 (m, 1H), 4.66 (s, 2H), 2.28 (s, 3H). [ES+MS] m/z 204 (M).
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[C:28]([NH:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])(=[O:30])[CH3:29].CC1C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[C:28]([NH:31][C:32]1[CH:33]=[C:34]([NH:35][C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=2)[CH:36]=[CH:37][CH:38]=1)(=[O:30])[CH3:29]
Reactant: Cn1cc(CNc2nc(On3nnc4ccccc43)ncc2C(N)=O)cn1
Reactant: CC(=O)Nc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCc3cnn(C)c3)n2)c1
Temperature: 100 °C
Yield: 75.1 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxamide (51 mg, 0.14 mmol) in NMP (0.8 mL) was added 3-acetamidoaniline (24 mg, 0.16 mmol) and pTsOH*H2O (27 mg, 0.14 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxamide (40 mg). MS found for C18H20N8O2 as (M+H)+ 381.5. λ=242.8.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5]C(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].C(N(CC)CC)C.C(OC)(OC)(OC)CCC.[CH2:35]([NH2:39])[CH:36]([CH3:38])[CH3:37]>O1CCCC1>[NH2:15][C:14]1[N:39]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:5]([CH2:6][CH2:1][CH3:11])=[N:12][C:13]=1[C:16]#[N:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)CN
Reactant: N#CC(N)C#N
Agent: CCCC(OC)(OC)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1nc(C#N)c(N)n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
Aminomalononitrile p-toluenesulfonate (15.0 g, 59.2 mmol) and triethylamine (9.08 mL, 71.1 mmol) were combined in tetrahydrofuran (THF) (200 mL) and stirred for 30 minutes; the reaction became homogeneous. Trimethyl orthobutyrate (11.4 mL, 71.1 mmol) was added, and the solution was heated at reflux for three hours. An analysis by TLC indicated the presence of starting material, and additional trimethyl orthobutyrate (5.0 mL) was added. The solution was heated at reflux for another 3.5 hours and allowed to cool to room temperature. A mixture of isobutylamine (7.06 mL, 71.1 mmol) and triethylamine (9.08 mL, 71.1 mmol) was added, and the reaction was stirred overnight. The majority of the THF was removed under reduced pressure, and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice with dichloromethane. The combined organic fractions were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to provide an orange solid that was triturated with ethyl acetate and isolated by filtration to provide 8.60 g (70%) of 5-amino-1-(2-methylpropyl)-2-propyl-1H-imidazole-4-carbonitrile as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[N:13][OH:14])=[CH:7][CH:6]=1.O1CCCC1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=3)[O:14][N:13]=2)=[CH:7][CH:6]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: ON=C(Cl)Cc1ccc(Oc2ccccc2F)nc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccccc4F)nc3)no2)cn1
Temperature: 50 °C
Reaction time: 5 h
Yield: 16.7 %

Procedure:
To a mixture of (6-(2-fluoro-phenoxy)-pyridin-3-yl)-acetohydroximoyl chloride (28 mg) described in Manufacturing Example 74-1-4 and tetrahydrofuran (1 mL) were added 5-ethynyl-pyridin-2-ylamine (9.0 mg, 0.076 mmol) described in Manufacturing Example 28-1-3 and triethylamine (21 μL, 0.15 mmol), which was stirred for 5 hours at 50° C. The reaction mixture was allowed to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (4.6 mg, 17%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:17](Br)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)=O>O.O1CCOCC1>[CH2:1]([NH:8][C:9]1[C:17]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(NCc2ccccc2)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: O=CO
Product: O=C(O)c1cnc(NCc2ccccc2)c(-c2ccc(Cl)cc2)c1
Temperature: 85 °C
Yield: 38.3 %

Procedure:
A mixture of 77 mg (0.25 mmol) 6-benzylamino-5-bromo-nicotinic acid, 58 mg (0.375 mmol) 4-chlorophenyl boronic acid, 9.1 mg 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium (II) dichloromethane complex 1:1 and 0.38 mL 2N Na2CO3 aq. in 0.5 mL water and 2 mL dioxane was heated to 85° C. for 20 h. Formic acid was added, filtered and the mixture was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/HCOOH. The combined product fractions were evaporated to yield 32.4 mg (38%) of the title compound. MS (m/e): 337.3 (M−H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:25][CH3:26])=[C:22]([OH:24])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:25][CH3:26])=[C:22]([CH:23]=1)[O:24][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: COc1ccc(N)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 36.1 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (800 mg, 2.44 mmol), 5-amino-2-methoxyphenol (408 mg, 2.93 mmol), potassium carbonate (843 mg, 6.10 mmol) and N,N-dimethylformamide (6.0 mL) as starting materials and in the same manner as in Example 91, the title compound (299 mg, 36%) was obtained as a brown powder.
Reaction SMILES: [CH2:1]([S:3]([C:5]1[CH:6]=[C:7]([C:21]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[N:22]=2)[C:8]([NH:11][C:12]2[CH:13]=[N:14][C:15]([O:19][CH3:20])=[C:16]([F:18])[CH:17]=2)=[N:9][CH:10]=1)=[O:4])[CH3:2].O.S(O)([O-])(=O)=[O:49].S(O)(OO)(=O)=O.[K+]>CO.O1CCOCC1>[CH2:1]([S:3]([C:5]1[CH:6]=[C:7]([C:21]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)[N:22]=2)[C:8]([NH:11][C:12]2[CH:13]=[N:14][C:15]([O:19][CH3:20])=[C:16]([F:18])[CH:17]=2)=[N:9][CH:10]=1)(=[O:49])=[O:4])[CH3:2]
Reactant: O=S(=O)([O-])O
Reactant: CCS(=O)c1cnc(Nc2cnc(OC)c(F)c2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Agent: O=S(=O)(O)OO
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)c1cnc(Nc2cnc(OC)c(F)c2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a slurry of 4-(5-(ethylsulfinyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.090 g, 0.140 mmol) in 2 mL MeOH, 2 mL dioxane, and 1 mL water was added potassium peroxymonosulfate sulfate (0.172 g, 0.280 mmol). The bright yellow slurry was stirred rapidly overnight. The reaction was partitioned between satd NaHCO3 and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (25 g column) using 20 to 100% EtOAc/hexane. The product-containing fractions were concentrated to afford 4-(5-(ethylsulfonyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.066 g, 0.100 mmol, 71.6% yield) as a yellow solid. m/z (ESI, +ve ion) 660 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.91 (s, 1H), 8.80 (d, J=2.7 Hz, 1H), 8.43 (d, J=2.7 Hz, 1H), 8.15-8.33 (m, 2H), 7.14-7.25 (m, 4H), 6.80-6.93 (m, 4H), 4.87 (s, 2H), 4.83 (s, 2H), 4.02 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.07-3.22 (m, 1H), 2.82-2.94 (m, 1H), 2.62 (s, 3H), 1.28 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Al+3].[Cl-:2].[Cl-].[Cl-].[C:5]([C:9]([C:12]([O:15][C:16]([C:22](F)=[O:23])([C:18]([F:21])([F:20])[F:19])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])([F:7])[F:6]>ClC1C=CC=CC=1Cl>[C:5]([C:9]([C:12]([O:15][C:16]([C:22]([Cl:2])=[O:23])([C:18]([F:21])([F:20])[F:19])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])([F:7])[F:6]
Reactant: [Cl-]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [Al+3]
Solvent: Clc1ccccc1Cl
Product: O=C(Cl)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 60 °C

Procedure:
A mixture of AlCl3 and o-dichlorobenzene (4 mL) was treated with CF3CF2CF2OCF(CF3)COF (13.2 g, 40 mmol) and heated at 60° C. for 0.5 hr. Volatiles were removed by vacuum transfer (27 Pa) to give a mixture of two liquids. The lower layer was separated and distilled to provide 8.0 g of colorless liquid, bp ca. 65° C. GC analysis showed 99% purity. 19F NMR (F11): -81.32 (s, CF3), -81.94 (t, J=7.3 Hz, CF3), -79.05 and -84.98 (AB pattern, J=146 Hz, OCF2), -126.1 (d of m's, J=23, CF), -130.1 (s, CF2).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH:7]([C:9]1[CH:10]=[C:11]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:12]=[C:13]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])[CH:14]=1)[CH3:8]>>[N:1]1([CH:7]([C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:19])[C:16]#[N:17])[CH:12]=[C:11]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:10]=2)[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CC(Cl)c1cc(C(C)(C)C#N)cc(C(C)(C)C#N)c1
Product: CC(c1cc(C(C)(C)C#N)cc(C(C)(C)C#N)c1)n1ccnc1

Procedure:
The process described in Example 8 was repeated, using imidazole in place of 1,2,4-triazole, and 2,2'-[5-(1-chloroethyl)-1,3-phenylene]di(2-methylpropiononitrile), (obtained as described in the second part of Example 7), as the starting materials, to give 2,2'-[5-(1-[imidazol-1-yl]ethyl)-1,3-phenylene]di(2-methylpropiononitrile), mp. 77°-80°.