Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15](B4OC(C)(C)C(C)(C)O4)[CH:16]=[C:11]3[CH:10]=[CH:9]2)=[CH:5][CH:4]=1.Br[C:29]1[CH:42]=[CH:41][C:32]([CH2:33][N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:42]4[CH:29]=[CH:30][CH:31]=[C:32]([CH2:33][N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)[CH:41]=4)[CH:16]=[C:11]3[CH:10]=[CH:9]2)=[CH:26][CH:27]=1
Reactant: CN1CCN(Cc2ccc(Br)cc2)CC1
Reactant: COc1ccc(Cn2ccc3cc(B4OC(C)(C)C(C)(C)O4)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc(Cn2ccc3cc(-c4cccc(CN5CCN(C)CC5)c4)cnc32)cc1
Temperature: 90 °C

Procedure:
A stirred solution of 1-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (147PG) (50 mg, 0.137 mmol) and 1-(4-bromobenzyl)-4-methylpiperazine (121) (37 mg, 0.137 mmol, 1.1 eq) in DME (10 mL) was degassed and purged with N2 for 10 min and Cs2CO3 (2.0 eq) was added and the reaction mixture purged and degassed again. To this reaction mixture was added Pd(PPh3)4 (0.04 eq) and the resulting reaction was heated at 90° C. for 12 hrs in sealed tube condition. After completion of the reaction the contents were was cooled and diluted with CH2Cl2 and filtered through Celite bed. The CH2Cl2 layer was completely distilled off to get the crude product. The crude was passed through 100-200 mesh silica gel, eluting the pure compound 1-(4-methoxybenzyl)-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine 151 obtained with 5% MeOH in CH2Cl2 as an off-white coloured solid in 30 mg quantity.
Reaction SMILES: COC1C=C(OC)C(OC)=CC=1C(N[C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1)=O.C(N(C(C)C)CCNC)(C)C.S([O-])(O)(=O)=O.[K+].C(OC(C)C)(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:16]([O:15][C:13]([C:11]1[N:12]=[CH:8][S:9][CH:10]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2OC)n1
Agent: CNCCN(C(C)C)C(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cscn1
Yield: 86 %

Procedure:
A suspension (1.5 ml) of 2-[N-(2,4,5-trimethoxybenzoyl)amino]-4-(ethoxycarbonyl)-1,3-thiazole (732 mg) and N,N-diisopropyl-N′-methylethylenediamine (1.60 g) in dimethylacetamide was stirred at 140° C. for 5 hours. To the reaction mixture, an aqueous solution of potassium hydrogensulfate, a small quantity of ethyl acetate, and a small quantity of isopropyl ether were added for precipitation of crystals. Crystals so precipitated were collected by filtration and dried to thereby obtain 601 mg of 2-[N-4,5-dimethoxy-2-hydroxybenzoyl)amino]-4-(ethoxycarbonyl)-1,3-thiazole (yield: 86%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH:23](B(O)O)=[CH2:24].C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1.[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>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH:23]=[CH2:24])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CB(O)O
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 100 °C

Procedure:
A suspension of (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Compound A1) (6.8 g, 20 mmol), vinyl boronic acid [CAS-No. 4363-34-2] {Bull. Soc. Chim. Fr. 8:2557–64 (1966)} (4.312 g, 60 mmol) and K2CO3 (8.29 g, 60 mmol) in water (10 mL) and dioxane (50 mL) was purged by Ar-stream at 23° C. for 10 min, then tetrakis(triphenylphosphine) palladium(0) (693 mg, 0.6 mmol) was added and the mixture was heated to 100° C. for 20 h, filtered, evaporated and purified by column chromatography on silica gel (hexane/ethyl acetate 9:1) to yield compound A15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[N:7][CH:8]=1.Cl[S:11]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:13])=[O:12]>N1C=CC=CC=1.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][S:11]([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])(=[O:13])=[O:12])[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(N)c1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1cncc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methoxypyridin-3-amine (1 eq) in pyridine (0.4 M) was added methyl 2-(chlorosulfonyl)benzoate (1 eq) and the mixture was stirred overnight at room temperature. The mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (0-8% MeOH/CH2Cl2) to give afford the title compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 10.56-10.66 (m, 1H) 8.55-8.61 (m, 1H) 7.95-8.01 (m, 1H) 7.86-7.94 (m, 1H) 7.67-7.73 (m, 2H) 7.34-7.40 (m, 1H) 7.02 (s, 1H) 3.83 (s, 3H) 3.73 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[CH:8]([CH2:9][CH3:10])[CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[OH-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[C@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CCC1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)OC
Temperature: 0 °C
Reaction time: 20 h
Yield: 44 %

Procedure:
N-[(tert-Butyloxy)carbonyl]-3-ethylproline methyl ester (29.1 g, 0.113 mol) was dissolved in CH3OH (114 mL) with cooling to 0° C., then treated with 1N NaOH (114 mL). After stirring for 20 h at 23° C., the solution was concentrated to remove the CH3OH and then extracted with EtOAc (3×). The organic layers were combined, dried (MgSO4), filtered, and concentrated to give 12.8 g of N-[(tert-Butyloxy)carbonyl]-cis-3-ethylproline methyl ester as an oil. The aqueous layer was acidified with solid citric acid and extracted with EtOAc (2×), the organic layers combined, dried (MgSO4), filtered, and concentrated to give 15.5 g of N-[(tert-Butyloxy)carbonyl]-trans-3-ethylproline as an oil. 1H NMR (CD3OD) δ3.86 and 3.78 (2 d, 1H, J=6 Hz), 3.33-3.58 (m, 2H), 2.01-2.22 (m, 2H), 1.5-1.74 (m, 2H), 1.33-1.5 (m, 1H), 1.45 and 1.42 (2 s, 9H), 0.98 (t, 3H, J=8 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=[O:2].[Cl-].[NH4+]>O1CCOCC1.[Zn]>[N:10]1([C:7]2[CH:6]=[CH:5][C:4]([NH:1][OH:2])=[CH:9][CH:8]=2)[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:12]=[CH:11]1
Reactant: O=[N+]([O-])c1ccc(-n2cnc3cnccc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1COCCO1
Product: ONc1ccc(-n2cnc3cnccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 3 mL of dioxane, 40 mg (0.167 mmol) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine obtained in Step A of Example 1 was dissolved, and 40 mg of zinc powder and 1 mL of a saturated ammonium chloride aqueous solution were added thereto and the mixture solution was vigorously stirred at room temperature for one hour. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with a sodium chloride solution, dried and then concentrated under reduced pressure to obtain a crude product of N-(4-imidazo[4,5-c]pyridine-1-ylphenyl)-hydroxylamine. The product was used in the next reaction without further purification.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.[NH2:12]C1NC=CN=1.Cl.[N+]([O-])([O-])=O.[Na+].[Br:24][CH2:25][CH2:26][N:27]([CH2:34][CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>O.C(O)(=O)C>[Br:24][CH2:25][CH2:26][N:27]([CH2:34][CH3:35])[C:28]1[CH:33]=[CH:32][C:31](/[N:12]=[N:6]/[C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)=[CH:30][CH:29]=1
Reactant: CCN(CCBr)c1ccccc1
Reactant: Nc1ncc[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCN(CCBr)c1ccc(/N=N/c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
1.32 g 2-amino-1H-imidazol-hemisulfate is diazotized in a mixture containing 2 ml hydrochloric acid, 2 ml acetic acid, 12 ml water and 0.7 g sodium nitrate at 5° C. Azo coupling is performed by adding 2.3 g N-(2-bromoethyl)-N-ethylaniline to the above diazonium solution. After stirring for 2 hours at room temperature the mixture is poured on 50 ml saturated sodium bicarbonate. The resulted precipitate is filtered off, washed with water, and dried in vacuum at 40° C. After chromatography on silicagel with ethylacetate, 0.6 g N-(2-bromoethyl)-N-ethyl-4-[(E)-1H-imidazol-2-yldiazenyl]aniline is obtained as a brown powder.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl.[CH3:14][NH:15][CH3:16].C(=O)(O)[O-].[K+].O>CN(C=O)C>[CH3:14][N:15]([CH3:16])[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc([N+](=O)[O-])cc1C#N
Temperature: 80 °C
Yield: 100 %

Procedure:
1.66 g (10.0 mmol) of 2-fluoro-5-nitrobenzonitrile, 1.22 g (15.1 mmol) of dimethylamine hydrochloride and 3.46 g (25.1 mmol) of potassium bicarbonate is dissolved, under an argon atmosphere, in DMF (30 ml) then the reaction medium is heated at a temperature of 80° C. for 18 hours. The reaction mixture is cooled down to 0° C. and ice-cooled water is added. The reaction mixture is extracted with ethyl acetate and the organic phase is washed successively with 50 ml of water and 50 ml of salt water, dried over magnesium sulphate, filtered and concentrated under vacuum. The evaporation residue is purified by trituration with isopropyl ether and the solid obtained is filtered and rinsed with isopentane in order to obtain after drying 2.0 g of a solid yellow product (yield 100%). Melting point: 109-110.5° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][CH:16]([CH3:19])[CH2:17]O>O1CCCC1>[CH3:19][C:16]1[NH:15][C:11]2[CH2:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][C:9](=[O:14])[C:10]=2[CH:17]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: CC(N)CO
Solvent: C1CCOC1
Product: Cc1cc2c([nH]1)CC(c1ccccc1)CC2=O
Temperature: 150 °C
Reaction time: 3.5 h
Yield: 66.8 %

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (4.0 g), 2-aminopropanol (2.1 g), molecular sieves 4A (24 g) and tetrahydrofuran (60 ml) was refluxed for 14 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (100 ml). To the solution were added 2-bromomesitylene (4.2. g), tetrakistriphenylphosphine palladium (0.6 g) and potassium carbonate (5.9 g), and the mixture was stirred at 150° C. for 3.5 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc), and the resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 2-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (3.2 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([F:38])[CH:32]=1>CN(C=O)C>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:2]2[C:7]([CH3:8])=[C:6]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=4)[CH2:12][CH2:11]3)[N:5]=[CH:4][N:3]=2)=[C:33]([F:38])[CH:32]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: Cc1c(Cl)ncnc1OC1CCN(c2nc(C(C)C)no2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(Br)cc2F)ncnc1OC1CCN(c2nc(C(C)C)no2)CC1
Temperature: 150 °C
Yield: 47.8 %

Procedure:
A mixture of 4-chloro-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine (1.51 g, 4.46 mmol), potassium carbonate (1.25 g, 9.03 mmol), and 4-bromo-2-fluorophenol (1.11 g, 5.82 mmol) in 15 mL DMF was heated in microwave for 1 hour at 150° C. The mixture was purified by column chromatography on silica gel with hexane/ethyl acetate (3:1 v/v) to give Compound C40 as an oil (1.05 g, 48%). 1H NMR (CDCl3, 400 MHz) δ 1.20-1.22 (d, 6H), 1.83-1.91 (m, 2H), 1.98-2.05 (m, 2H), 2.11 (s, 3H), 2.77-2.87 (m, 1H), 3.53-3.59 (m, 2H), 3.74-3.80 (m, 2H), 5.31-5.36 (m, 1H), 6.99-7.03 (m, 1H), 7.22-7.29 (m, 2H), 8.13 (s, 1H). Exact mass calculated for C21H23BrFN5O3 491.1, found 492.4 (MH+).
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].[F:6][C:7]([F:17])([F:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.C([O-])(=O)C.[NH4+].C(OC(=O)C)C>CCCCCC>[N+:1]([C:4]([CH3:5])=[CH:12][C:11]1[CH:14]=[CH:15][C:8]([C:7]([F:17])([F:16])[F:6])=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=Cc1ccc(C(F)(F)F)cc1)[N+](=O)[O-]
Temperature: 115 °C
Yield: 42.9 %

Procedure:
Nitro ethane (30.94 mL, 430.73 mmol) was added to 4-trifluoromethyl-benzaldehyde (5 g, 28.71 mmol) and ammonium acetate (6.64 g, 86.15 mmol) and the resulting mixture was refluxed at 115° C. overnight. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mass was cooled and partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated. Purification by column chromatography on silica gel (2% ethylacetate in hexane) afforded 2.85 g of the product (42.93% yield).
Reaction SMILES: Cl.C1(C)C=CC(NN)=CC=1.BrCC(OC)=O.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])N)=[CH:20][CH:19]=1.C(OC(OCC)CCCNC)C.CC1C=C2[C:50](=[CH:51][CH:52]=1)[N:49]([CH2:53][C:54](OC)=O)[CH:48]=C2CCNC.C=O.C(O)(C(F)(F)F)=O>C(#N)C.C(N(CC)CC)C>[CH3:48][N:49]1[CH2:53][CH2:54][C:52]2[C:22]3[C:21](=[CH:20][CH:19]=[C:18]([CH3:17])[CH:23]=3)[N:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:51]=2[CH2:50]1
Reactant: COC(=O)CN(N)c1ccc(C)cc1
Reactant: CNCCc1cn(CC(=O)OC)c2ccc(C)cc12
Agent: C=O
Agent: CCOC(CCCNC)OCC
Agent: COC(=O)CBr
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)Cn1c2c(c3cc(C)ccc31)CCN(C)C2

Procedure:
The title compound is prepared by following General Methods 1, 3, and 4 by using p-tolylhydrazine hydrochloride, methyl bromoacetate, and triethylamine (General Method 1), methyl 2-(1-(4-methylphenyl)hydrazinyl)acetate and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3), and methyl 2-(5-methyl-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[CH:14]\[C:15]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[CH2:17][CH2:16]2)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][CH:15]([C:18]2[CH:19]=[C:20]([F:25])[CH:21]=[C:22]([F:24])[CH:23]=2)[CH2:16][CH3:17])[CH2:11][O:10][C:9]1([CH3:26])[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@@H](/C=C\C2(c3cc(F)cc(F)c3)CC2)COC1(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCC(CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a stirred solution of (S)-4-{(Z)-2-[1-(3,5-difluoro-phenyl)-cyclopropyl]-vinyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.5 g) at room temperature in methanol (10 ml) under an argon atmosphere were added palladium on charcoal (10%, 30 mg) and ammonium formate (1.33 g). The mixture was stirred at room temperature overnight. The catalyst was filtered off, the filtrate was concentrated, ethyl acetate was added and the mixture was washed with water. The organic layer was separated, dried over magnesium sulphate and concentrated to give (S)-4-[3-(3,5-difluoro-phenyl)-pentyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.5 g) as a light yellow liquid. MS (ISP): 384.3 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:24])[N:12]([CH3:23])[C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][CH:15]=1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[CH:32]=[C:33]([I:35])[S:34][C:27]=12>CN(C1C=CN=CC=1)C.BrC1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:26]2[CH:31]=[CH:30][N:29]=[C:28]3[CH:32]=[C:33]([I:35])[S:34][C:27]=23)[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:24])[N:12]([CH3:23])[C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][CH:15]=1
Reactant: Clc1ccnc2cc(I)sc12
Reactant: Cn1c(Nc2ccccc2)ncc(-c2cc(F)c(O)cc2F)c1=O
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Product: Cn1c(Nc2ccccc2)ncc(-c2cc(F)c(Oc3ccnc4cc(I)sc34)cc2F)c1=O

Procedure:
A mixture of 5-(2,5-difluoro-4-hydroxyphenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.031 g, 0.093 mmol), 7-chloro-2-iodothieno[3,2-b]pyridine (0.025 g, 0.085 mmol; prepared according to the procedure of Ragan, J. A. Org. Proc. Res. 2003, 7, 676) and DMAP (0.010 g, 0.085 mmol) in bromobenzene (1.5 mL) under nitrogen was stirred at 150° C. for 6 days. The reaction was concentrated in vacuo to remove as much bromobenzene as possible and then purified directly by flash column chromatography, eluting with 20:1 CH2Cl2/MeOH. The product was obtained (10.5 mg; 21%) as a yellow solid. LRMS (APCI pos) m/e 589 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]([NH2:13])=[S:12].Cl[CH:15]([C:20](=O)[CH2:21][CH3:22])[C:16]([O:18][CH3:19])=[O:17]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[S:12][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:20]([CH2:21][CH3:22])[N:13]=1
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: NC(=S)Nc1c(Cl)cc(Cl)cc1Cl
Solvent: CCO
Product: CCc1nc(Nc2c(Cl)cc(Cl)cc2Cl)sc1C(=O)OC

Procedure:
A stirred solution of 2,4,6-trichlorophenylthiourea (scheme 1: (B)) (3.25 g, 12.72 mmoles) and methyl 2-chloro-3-oxopentanoate (Scheme 1: (C)) (1.92 mL, 1.1 equiv.) in ethanol (60 mL) was heated at reflux for 16 hours. The solvent was removed in vacuo and the product was recrystallized from methanol (4.49 g, 97%). H1 NMR (CDCl3) δ 1.15 (3H, t), 2.91 (2H, q), 3.75 (3H, s), 7.47 (2H, s), 9.10 (1H, br).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:23][C:20]2[S:21][CH:22]=[C:18]([CH3:17])[N:19]=2)[CH:7]=1
Reactant: COc1cccc(Oc2ccnc(Cl)c2)c1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(Oc2ccnc(Nc3nc(C)cs3)c2)c1
Yield: 96.3 %

Procedure:
Using the method of Example 3, Step B, 2-chloro-4-(3-methoxyphenoxy)pyridine (2.95 g, 12.5 mmol), 4-methylthiazol-2-amine (28.5 mL, 11.4 mmol), potassium phosphate (2.66 g, 12.5 mmol), Pd2(dba)3 (0.261 g, 0.285 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.181 g, 0.313 mmol) were reacted in toluene (30 mL) and water (8 mL) to provide 4-(3-methoxyphenoxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (3.44 g, 88.7% yield) as yellow solid. 1H NMR (CDCl3) δ 8.14 (d, 1H), 7.26 (t, 1H), 6.76 (m, 1H), 6.63 (m, 1H), 6.58 (t, 1H), 6.46 (dd, 1H), 6.27 (m, 2H), 3.75 (s, 3H), 2.17 (s, 3H); Mass spectrum (esi) m/z=314 (100) (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[CH:9]=[CH:10][N:11]=2)=[CH:3][CH:2]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[N:30]=[C:31]=[O:32]>C(Cl)Cl.CN(C=O)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[NH:30][C:31]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:13][CH:14]=1)=[O:32]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(-n2ccnc2-c2ccncc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-n2ccnc2-c2ccncc2)cc1)Nc1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-Pyridin-4-yl-imidazol-1-yl)-phenylamine (100 mg, 0.424 mmol) in DCM (4.0 mL) and DMF (1.0 mL) is added 1-fluoro-2-isocyanato-4-trifluoromethyl-benzene (91 mg, 0.445 mmol, 1.05 equiv) and allowed to stir for 2 h at RT. All solvent is then removed under reduced pressure and the resulting solid was purified by column chromatography (5% MeOH:95% DCM) to afford 1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[4-(2-pyridin-4-yl-imidazol-1-yl)-phenyl]-urea as an off-white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:13]1[C:17]2[C:18]([Cl:22])=[N:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1)[C:10]#[C:11][CH3:12].[Cl:23]C(Cl)(Cl)C(Cl)(Cl)Cl.[Cl-].[NH4+]>O1CCCC1>[CH2:9]([N:13]1[C:17]2[C:18]([Cl:22])=[N:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[Cl:23])[C:10]#[C:11][CH3:12]
Reactant: CC#CCn1cnc2ccnc(Cl)c21
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC#CCn1c(Cl)nc2ccnc(Cl)c21
Reaction time: 0.33 h
Yield: 21 %

Procedure:
2.22 ml of a tetrahydrofuran solution of lithium diisopropylamide was added dropwise to a 5 ml tetrahydrofuran solution of 490 mg of 3-(2-butynyl)-4-chloro-3H-imidazo[4,5-c]pyridine in a dry ice-methanol bath, and the mixture was stirred below −66° C. for 20 minutes. The resulting reaction mixture was added dropwise to a 2 ml tetrahydrofuran solution of 1.13 g of hexachloroethane while the temperature of the mixture was controlled to be −63° C. or lower. The mixture was stirred for one hour and 40 minutes in the same bath, and then a saturated aqueous ammonium chloride solution was added thereto. The resulting mixture was extracted twice with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. Then, the resulting residue was purified by silica gel column chromatography. Thus, 120 mg of brown oily material was obtained from the fraction eluted with hexane-ethyl acetate (2:1).