Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:43][O:42][CH2:41]3)=[CH:36][CH:35]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:20]1([C:3]2[N:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]4[N:16]=[CH:17][CH:18]=[CH:19][C:7]=4[N:6]3[C:2]=2[C:34]2[CH:35]=[CH:36][C:37]([C:40]3([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[CH2:43][O:42][CH2:41]3)=[CH:38][CH:39]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)COC1
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)COC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
A suspension of 3-bromo-2-phenyl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepine (50 mg) and tert-butyl {3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-yl}carbamate (96 mg) and potassium phosphate (82 mg) and PdCl2(dppf)CH2Cl2 (11 mg) in dioxane (2.5 mL) and H2O (0.25 mL) was degassed for 5 min then stirred at 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (5-100% ethyl acetate in hexanes) gave the product (58 mg, 81%). 1HNMR (DMSO-d6) 400 MHz δ: 8.57 (s, 1H), 8.16-7.83 (m, 3H), 7.55-7.44 (m, 4H), 7.39-7.21 (m, 7H), 7.15-7.09 (m, 1H), 6.98-6.84 (m, 1H), 6.68 (dd, J=7.8, 4.6 Hz, 1H), 4.87-4.75 (m, 2H), 4.73-4.60 (m, 2H), 1.57-1.03 (m, 9H). LCMS: 558 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].C(N(CC)CC)C.[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:43](=[O:44])[C:42]4[CH:46]=[CH:47][C:39]([F:38])=[CH:40][CH:41]=4)[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Oc1cc(-c2cn(C3CCN(C(=O)c4ccc(F)cc4)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h

Procedure:
The product of the above mentioned Example 2 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) was added to N,N-dimethyl formamide (10 mL), triethylamine (404 mg, 4 mmol) and p-fluorobenzoyl chloride (475.5 mg, 3 mmol) were added, and the reaction was performed overnight at room temperature. The resultant mixture was washed with water for several times, dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane/methanol=15:1) to yield the target product as white solid powder.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:8]([C:7]1[C:2]([O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: O=[N+]([O-])c1cccnc1Oc1ccccc1

Procedure:
In step (3) of Reaction Scheme IV a 2-chloro-3-nitropyridine of Formula XXIV is reacted with phenol to provide a 3-nitro-2-phenoxypyridine of Formula XXV. Phenol is reacted with sodium hydride in a suitable solvent such as diglyme or tetrahydrofuran to form the phenoxide. The phenoxide is then reacted at ambient temperature, or optionally at an elevated temperature, with a compound of Formula XXIV.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(NC(C)C)(C)C.[C:34](Cl)(=[O:36])[CH3:35]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][C:34](=[O:36])[CH3:35])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: CC(=O)Cl
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc(NC(C)=O)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.8 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in tetrahydrofuran (4 mL) were added N,N-diisopropylamine (111 mg, 0.86 mmol), 4-dimethylaminopyridine (7.0 mg, 0.06 mmol) and acetyl chloride (59 mg, 0.75 mmol) and the reaction mixture was stirred at ambient temperature for 6 h. The resulting suspension was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with aqueous sodium carbonate (saturated). Drying over sodium sulfate and concentration afforded the title compound (162 mg, 72%) as a yellow solid. MS: m/e=391.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:5][OH:6])[C:7]([F:10])=[CH:8][CH:9]=1
Reactant: O=Cc1c(F)ccc(Br)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1c(F)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
20 g of 3-bromo-2,6-difluorobenzaldehyde are dissolved in 450 ml of methanol and cooled in an ice bath; 3.42 g of sodium borohydride are then added thereto, portionwise. The mixture is stirred at ambient temperature for 1 hour and the solvent is then evaporated off under reduced pressure. The residue is taken up between water and dichloromethane. The organic phase is separated, dried and concentrated under reduced pressure. The residue is crystallized from n-pentane. 14.6 g of compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:19][N:18]([C:20](OC(C)(C)C)=[O:21])[CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:30][CH3:31])[CH:3]=1.[CH2:32](N(CC)CC)[CH3:33].C(Cl)(=O)C=C>Cl.CO.C(Cl)Cl>[C:20]([N:18]1[CH2:17][CH:16]([N:13]2[CH2:14][CH2:15][CH:10]([C:8]([NH:7][CH2:6][C:5]3[CH:27]=[C:28]([Cl:29])[C:2]([Cl:1])=[CH:3][C:4]=3[O:30][CH3:31])=[O:9])[CH2:11][CH2:12]2)[CH2:19]1)(=[O:21])[CH:32]=[CH2:33]
Reactant: COc1cc(Cl)c(Cl)cc1CNC(=O)C1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Reactant: CCN(CC)CC
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C=CC(=O)N1CC(N2CCC(C(=O)NCc3cc(Cl)c(Cl)cc3OC)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A mixture of tert-butyl 3-(4-(4,5-dichloro-2-methoxybenzylcarbamoyl)piperidin-1-yl)azetidine-1-carboxylate (210 mg, 0.44 mmol) in HCl/MeOH (10 mL, 2.86 M) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to yield the crude residue. The residue was dissolved in DCM (5 mL), triethylamine (0.5 mL) and acryloyl chloride (40 mg, 0.43 mmol) were added. The reaction mixture was stirred at room temperature for 30 min and then partitioned between DCM and water. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (150 mg, 82% yield).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH2:24]([NH2:27])[CH2:25][CH3:26]>C(O)C>[CH2:24]([NH:27][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1)[CH2:25][CH3:26]
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: CCCN
Solvent: CCO
Product: CCCNc1ncc2c(=O)[nH]c(-c3ccccc3OCCC)nc2n1

Procedure:
In a similar manner to Example 34 reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) and n-propylamine (1.44 g) in ethanol (20 ml) yielded the title compound, 0.46 g, m.p. 185.7° C. (recrystallized from ethanol).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[N:12]1([CH2:18][CH2:19][OH:20])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH2:18][CH2:19][OH:20])[CH2:13][CH2:14]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1cc(N2CCN(CCO)CC2)ccc1[N+](=O)[O-]
Temperature: 122.5 °C
Reaction time: 24 h
Yield: 77.7 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (5.0 g, 29.0 mmol), 2-piperazin-1-yl-ethanol (11.3 g, 87.0 mmol) and anhydrous potassium carbonate (4.4 g, 31 mmol) in N,N-dimethylacetamide (10 ml) was stirred at 120-125° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (30 ml) and stirred vigorously and cooled at 5° C. overnight. The resulting yellow precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting yellow brown solid was slurried in diethyl ether (30 mL), filtered, washed with additional diethyl ether, dried to afford 2-[4-(3-Amino-4-nitro-phenyl)-piperazin-1-yl]-ethanol (6.0 g, 77%) as a yellow powder.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][S:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)(=[O:15])=[O:14]>>[NH2:11][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][S:13]([CH3:12])(=[O:14])=[O:15])=[CH:22][CH:21]=3)[N:7]2[N:8]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Product: CS(=O)(=O)Nc1ccc(-c2cccc3nc(N)nn23)cc1
Yield: 15.2 %

Procedure:
N-[4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.80 g, 8.45 mmol) and 4-methylsulfonylaminophenyl boronic acid (2.0 g, 9.30 mmol), in a manner analogous to Step 73c. The residue was purified on a 40 g Isco silica gel column using a gradient of 0-15% methanol in dichloromethane as an eluent. N-[4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide (389 mg, 15%) was isolated as a beige powder. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.06 (s, 1H), 7.96 (d, J=10.7 Hz, 2H), 7.49 (t, J=17.1 Hz, 7.5 Hz, 1H), 7.34 (d, J=8.6 Hz, 3H), 7.00 (d, J=7.5 Hz, 1H), 6.01 (s, 2H), 3.09 (s, 3H). MS=304 (MH)+.
Reaction SMILES: [C:1]1([CH:7]([CH2:10][CH2:11][CH2:12][CH3:13])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:16][C:17]([CH2:19]Cl)=[CH2:18]>CN(C)C=O>[CH2:10]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:19][C:17]([Cl:16])=[CH2:18])[C:8]#[N:9])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(C#N)c1ccccc1
Reactant: C=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(Cl)CC(C#N)(CCCC)c1ccccc1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
A 7.62 g. portion of 2-phenylhexanenitrile and 2.11 g. of 50% sodium hydride were combined in 30 ml. of dry dimethylformamide, and the mixture was stirred for 1.5 hours at 50°-55° C. The mixture was then cooled to 20° C. and 4.88 g. of 2,3-dichloro-1-propene was added dropwise, followed by an additional 10 ml. of dry dimethylformamide. The reaction mixture warmed spontaneously to about 35° C., and it was warmed to 55° C. after the addition and was stirred at that temperature for 1.5 hours. The mixture was then allowed to cool to ambient temperature and was stirred for 64 hours. It was then filtered to remove insoluble inorganics, and the solids were washed with ethyl acetate. The filtrate was evaporated under vacuum to an oil, which was dissolved in diethyl ether and was washed with water. The residue was taken up in ethanol and evaporated to dryness under vacuum to obtain 10.85 g. of the crude product named in the heading above. The product was identified by 60 mHz nuclear magnetic resonance analysis in CDDl3 : δ7.37 (m, 5H); 5.25 (d, 1H, J=2 Hz); 5.08 (d, 1H, J=2 Hz); 2.93 (s, 2H); 1.97 (dt, 2H); 1.25 (m, 4H); 0.83 (t, 3H).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CN1CCCC1=O.O.C(O)=O.[Cu]Cl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:15]2[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:2])=[O:20])=[O:19])=[CH:13][CH:14]=2)=[CH:24][CH:23]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(I)cc1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: O
Solvent: O=CO
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccccc1C(=O)O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 106.5 %

Procedure:
To 2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3] (50 mg) in 1-methyl-2-pyrrolidinone (1 mL) was added 4-fluorophenol (29.4 mg), copper (I) chloride (6.6 mg), cesium carbonate (85 mg) and 8-hydroxy-chinolin (4.7 mg). The reaction mixture was stirred at 120° C. for 18 hours. After such time, the reaction mixture was allowed to cool down to room temperature, diluted with water, formic acid was added (0.3 mL) and the solution was purified by preparative HPLC to yield 2-[4-(4-fluoro-phenoxy)-benzoylamino]-benzoic acid (49.1 mg). MS (m/e): 332.1 (M−H−, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)[CH:5]=[CH:6][C:7]=1/[CH:8]=[CH:9]/[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][N:11]=1.[C:28]1(=O)[O:33][C:31](=[O:32])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.C(N(CC)CC)C.O>CC1C=CC(C)=CC=1>[OH:27][CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][N:19]([C:4]2[CH:5]=[CH:6][C:7](/[CH:8]=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][N:11]=3)=[C:2]([N:1]3[C:31](=[O:32])[C:30]4[C:29](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:28]3=[O:33])[CH:3]=2)[CH2:24][CH2:23]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(N2CCN(CCO)CC2)ccc1/C=C/c1n[nH]c2ccccc12
Solvent: O
Solvent: Cc1ccc(C)cc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1c1cc(N2CCN(CCO)CC2)ccc1/C=C/c1n[nH]c2ccccc12
Temperature: 140 °C
Reaction time: 25 h
Yield: 3.3 %

Procedure:
(E)-2-(4-{3-amino-4-[2-(1H-indazol-3-yl)vinyl]phenyl}piperazin-1-yl)ethanol (0.10 g, 0.28 mmol) obtained in Step 3 of Example 273 was dissolved in p-xylene (3.5 mL) and the solution was added with phthalic anhydride (49 mg, 0.33 mmol), triethylamine (0.02 mL, 0.14 mmol), molecular sieves 3A (0.10 g), followed by stirring at 140° C. for 25 hours. The solution was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The filtrate was reslurried with ethyl acetate to obtain Compound 299 (4.5 mg, 3%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:20][C:21]1[N:25]([CH3:26])[C:24](=[O:27])[C:23]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[C:42](Br)[CH:41]=2)([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[C:30]([F:39])[CH:29]=2)[N:22]=1.[N:48]1[CH:53]=[C:52](B(O)O)[CH:51]=[N:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+]>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].O.COCCOC>[NH2:20][C:21]1[N:25]([CH3:26])[C:24](=[O:27])[C:23]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[C:42]([C:52]3[CH:53]=[N:48][CH:49]=[N:50][CH:51]=3)[CH:41]=2)([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[C:30]([F:39])[CH:29]=2)[N:22]=1
Reactant: OB(O)c1cncnc1
Reactant: CN1C(=O)C(c2ccc(OC(F)(F)F)c(F)c2)(c2ccc(F)c(Br)c2)N=C1N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CN1C(=O)C(c2ccc(OC(F)(F)F)c(F)c2)(c2ccc(F)c(-c3cncnc3)c2)N=C1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
A mixture of ethylene glycol dimethyl ether, tris(dibenzylideneacetone)-dipalladium(0) (0.015 g, 16.5 μmol) and triphenylphosphine (0.008 g, 32.0 μmol) under nitrogen is stirred for 5 min, treated with 2-amino-5-(3-bromo-4-fluorophenyl)-5-[3-fluoro-4-(trifluoromethoxy)phenyl]-3-methyl-3,5-dihydroimidazol-4-one (0.154 g, 0.33 mmol), 5-pyrimidine boronic acid (0.046 g, 0.37 mmol), sodium carbonate (0.105 g, 0.99 mmol) and water, heated at reflux temperature for 1.25 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica, 95:5:0.5 methylene chloride/methanol/concentrated ammonium hydroxide as eluent) to afford a viscous oil. This oil is suspended in a mixture of methylene chloride/hexanes and concentrated to afford the title compound as an off-white solid, 0.045 g (29% yield), mp 102-110° C., identified by HNMR and mass spectral analyses. 1H NMR (500 MHz, CD3OD) δ 9.15 (s, 1H), 8.95 (s, 2H), 7.62-7.56 (m, 2H), 7.39-7.27 (m, 4H), 3.12 (s, 3H); IR 3353, 3061, 2956, 1732, 1668, 1498, 1470, 1416, 1251, 1216, 1170 cm−1; ESI MS m/z 464 [C21H14F5N5O2+H]+; HPLC (Method 2) 95.0% (AUC) tR=13.78 min.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:11]1([SH:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.Cl[C:18]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=2)[N:21]=[CH:20][C:19]=1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>CN(C=O)C.CCOC(C)=O>[CH:11]1([S:16][C:18]2[N:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=3)[N:21]=[CH:20][C:19]=2[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: SC1CCCC1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2SC2CCCC2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
Sodium bis(trimethylsilyl)amide (7.13 mL, 7.13 mmol) was added dropwise to cyclopentanethiol (0.761 mL, 7.13 mmol) in DMF (25 mL) under nitrogen. The resulting solution was stirred at 20° C. for 30 minutes. A solution of tert-butyl 5-chloro-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate (Intermediate #9) (2 g, 5.94 mmol) in DMF (10 mL) was then added dropwise and the resulting mixture was stirred at 20° C. for to 2 hours. The reaction mixture was diluted with EtOAc (200 mL), and washed sequentially with water (4×50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate (1.380 g, 57.7%) as a colourless oil which crystallised on standing.
Reaction SMILES: [CH3:1][N:2]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[N:12]=[C:11]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[C:10](B(O)O)=[CH:9][CH:8]=1)=[O:5].I[C:37]1[N:41]2[CH:42]=[CH:43][C:44]([CH3:46])=[CH:45][C:40]2=[N:39][C:38]=1[C:47]1[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:32]([O:31][C:29](=[O:30])[N:2]([CH3:1])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:37]2[N:41]3[CH:42]=[CH:43][C:44]([CH3:46])=[CH:45][C:40]3=[N:39][C:38]=2[C:47]2[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=2)=[C:11]([C:13]#[C:14][Si:15]([CH:19]([CH3:20])[CH3:21])([CH:22]([CH3:23])[CH3:24])[CH:16]([CH3:18])[CH3:17])[N:12]=1)=[O:5])([CH3:34])([CH3:33])[CH3:35]
Reactant: Cc1ccn2c(I)c(-c3ccncc3)nc2c1
Reactant: CC(C(=O)Nc1ccc(B(O)O)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccn2c(-c3ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc3C#C[Si](C(C)C)(C(C)C)C(C)C)c(-c3ccncc3)nc2c1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of [6-[2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoylamino]-2-[2-tri(propan-2-yl)silylethynyl]pyridin-3-yl]boronic acid D1a (1.5 g, 3.0 mmol), 3-iodo-7-methyl-2-pyridin-4-ylimidazo[1,2-a]pyridine Za (1.3 g, 3.9 mmol), Na2CO3 (0.95 g, 8.9 mmol), Dichlorobis(triphenylphosphine)palladium(II) (209 mg, 0.3 mmol), dioxane (30 ml) and water (5 ml) is stirred under argon atmosphere for 17 h at 70° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 965 mg (49%). HPLC-MS: M+H=667; tR=2.04 min (*Method—3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[I:20]I>C1COCC1.CCCCC>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[I:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnccc1I
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of (pyridin-3-yl)-carbamic acid tert-butyl ester (prepared according to the procedure described in Tetrahedron Lett. 1994, 35, 9003) (2.2 g, 11.3 mmol) in 20 mL of THF at −78° C. is added dropwise t-BuLi (15.4 mL of a 1.7 M solution in pentane, 26 mmol). After 15 minutes, the solution is warmed to −10° C. for 3 hours. The mixture is cooled to −78° C. and a solution of iodine (5.7 g, 22.4 mmol) in 20 mL of THF is added via syringe. The resulting mixture is stirred at −78° C. for 1 hour, then allowed to warm to room temperature and quenched with saturated NH4Cl solution. The aqueous layer is extracted with EtOAc (2×). The combined organic layers are washed with 1 N HCl, water, dilute Na2S2O3, saturated NaHCO3 and saturated NaCl. The organic layer is then dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 5% EtOAc/CH2Cl2 to 20% EtOAc/CH2Cl2 to yield the title compound (1.3 g, 4.06 mmol) as a brown solid.