Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=2)=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.O>[F:24][C:16]1[CH:15]=[C:14]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)=[CH:3][CH:4]=3)[C:12]([CH3:13])=[CH:11][CH:10]=2)[CH:19]=[CH:18][C:17]=1[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: OB(O)c1ccco1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(-c2ccco2)cc1
Yield: 60.7 %

Procedure:
To a stirred suspension of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole (0.41 g, 1 mmol), 2-furanboronic acid (0.14 g, 1.26 mmol), NaHCO3 (0.19 g, 2.3 mmol) in DME-water (6 mL-2 mL) was added dichlorobis(triphenylphosphine) palladium (80 mg, 0.115 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 6 hours. After cooling, volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/2) to give the title compound (0.24 g, 61% yield).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:14])[CH:3]=1.[CH2:15]([OH:17])[CH3:16]>>[CH2:15]([O:17][C:6](=[O:7])[C:5]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([NH2:1])=[CH:3][C:4]=1[F:14])[CH3:16]
Reactant: Nc1cc(F)c(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: CCO
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Yield: 89 %

Procedure:
A solution of the product obtained at 149e (1.4 g, 6.4 mmol) in 50 mL ethanol was heated to reflux for 2 h. The mixture was filtered and the filtrate concentrated i.vac. The residue is reacted without any further purification. Yield: 89%.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=O>[Pd].C(O)(=O)C.C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[CH2:10][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(C(=O)c2ccncc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cccc(Cc2ccncc2)c1
Yield: 98.8 %

Procedure:
Ammonium formate (25 g) was added to a mixture of 4-(3-methoxybenzoyl)pyridine (27 g, 127 mmol) and 10% palladium on charcoal (7 g) in acetic acid (250 ml). The mixture was heated at reflux for 0.5 hr. The mixture was cooled and diluted with an equal volume of methylene chloride. The catalyst was removed and the solution concentrated in vacuo. The residue was dissolved in water and basified with sodium hydroxide. The mixture was extracted with ether. The extracts were dried and concentrated in vacuo to give the crude 4-(3-methoxybenzyl)pyridine (25 g, 99%) which was used without purification in the next step.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([C:24]([OH:31])([CH3:30])[CH:25]([O:28][CH3:29])[O:26][CH3:27])=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:44].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:44][C:17]([C:19]4[S:20][C:21]([C:24]([OH:31])([CH3:30])[CH:25]([O:28][CH3:29])[O:26][CH3:27])=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: COC(OC)C(C)(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(OC)C(C)(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(1-hydroxy-2,2-dimethoxy-1-methylethyl)-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (1.14 g), ammonium acetate (0.76) and acetic acid (8 mL) was stirred at 100° C. for 1 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.55 g, yield 50%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 561 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=O)[CH:10]=[CH:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[O:15]1[CH2:16][CH2:17][CH:12](/[CH:11]=[CH:10]/[C:9]2[NH:8][C:7]3[CH:6]=[CH:5][C:4]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[CH:3][C:2]=3[N:1]=2)[CH2:13][CH2:14]1
Reactant: Nc1cc(-c2ccccc2C(F)(F)F)ccc1NC(=O)C=CC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1-c1ccc2[nH]c(/C=C/C3CCOCC3)nc2c1
Temperature: 100 °C
Reaction time: 0.04 h

Procedure:
A mixture of N-(3-amino-2′-trifluoromethyl-biphenyl-4-yl)-3-(tetrahydro-pyran-4-yl)-acrylamide (76.0 mg, 0.195 mmol, as prepared in the previous step) in toluene (5 mL) was treated with p-toluenesulfonic acid (74.2 mg, 0.390 mmol) and heated to 100° C. under a reflux condenser for 4 h. The cooled mixture was treated with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g Sepra Si 50 SPE column (Isco system: flow rate=20 mL/min; Eluent=1% MeOH—CH2Cl2 for 0-5 min, then 1-4% MeOH—CH2Cl2 for 5-25 min). The resulting residue was purified by RP-HPLC (C18) eluting with CH3CN, 0.1% TFA/water, 10:90 to 50:50, v/v over a period of 20 minutes. The desired column fractions were treated with saturated aqueous NaHCO3 to pH 7 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo to yield (E)-2-[2-(tetrahydro-pyran-4-yl)-vinyl]-5-(2-trifluoromethyl-phenyl)-1H-benzimidazole as a pale yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](C(=O)C)[CH:9]=[CH:10][C:3]=12.C[O-].[Na+].CO>C(O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: CC(=O)n1ccc2c(I)ccnc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Ic1ccnc2[nH]ccc12
Yield: 234.2 %

Procedure:
Compound 2 (2.7 g, 18 mmol) and NaI (13 g, 88 mmol) were dissolved in acetonitrile (28 ml). To this solution, CH3COCl (3.5 ml, 50 mmol) was added while stirring at room temperature. The reaction mixture was heated at 85° C. for 12 hours. After the reaction mixture was cooled to room temperature, 10% aqueous Na2CO3 (28 ml) and 10% aqueous NaHSO3 (28 ml) were added sequentially and stirred at room temperature for 15 minutes. The reaction mixture was washed with ethyl acetate, and the organic layer was further washed with saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the organic layer was concentrated and purified on a silica gel column to give 4-iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g) and 4-iodo-1H-pyrrolo[2,3-b]pyridine (Compound 3) (2.3 g). 4-Iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g, 7.0 mmol) was dissolved in ethanol (70 ml) and, after addition of 28% sodium methoxide in methanol (1.4 ml, 7.0 mmol), was then heated under reflux for 1 hour. The reaction mixture was concentrated and then partitioned between ethyl acetate and saturated aqueous ammonium chloride, and the organic layer was washed with saturated aqueous ammonium chloride. After drying over anhydrous sodium sulfate, the organic layer was concentrated and combined with Compound 3 (2.3 g) which had been previously obtained, followed by recrystallization from ethanol to give Compound 3 (4.0 g, 92%).
Reaction SMILES: C(OC([N:8]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:9][C:10]([N:12]1[CH2:35][CH2:34][CH2:33][C@H:13]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH:21]([OH:32])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:15])=[O:11])=O)(C)(C)C>Cl.O1CCOCC1>[OH:32][CH:21]([C@@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:14](=[O:15])[C@@H:13]1[CH2:33][CH2:34][CH2:35][N:12]1[C:10](=[O:11])[CH2:9][NH:8][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CN(C(=O)OC(C)(C)C)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
(2S)-1-{N-[N-(tert-Butoxycarbonyl)-N-phenylglycyl]-L-prolyl}-2-[1-hydroxy-2-(4-methoxyphenoxy)ethyl]pyrrolidine (656 mg) was dissolved in 4N hydrochloric acid/1,4-dioxane (5 ml) and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated, and the resultant residue was dissolved in saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 518 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH2:8][CH2:7][C:6](=[O:9])[C:5]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>[Pd]>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC1=C(COC)CCC1=O
Agent: [Pd]
Product: CCCCCC1C(=O)CCC1COC

Procedure:
Using a standard autoclave pressure reactor 3-(methoxymethyl)-2-pentylcyclopent-2-en-1-one (0.5 mol) was hydrogenated at 100° C. and 200 pounds per square inch using 5% palladium on carbon as a catalyst. After filtration, 3-(methoxymethyl)-2-pentylcyclopentan-1-one was obtained as was confirmed by the following data;
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][C:16]1[N:21]=[C:20]([CH2:22]O)[CH:19]=[CH:18][N:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:22][C:20]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:15])[N:21]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1nccc(CO)n1
Reactant: O=[N+]([O-])c1ccc(O)c2ccccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nccc(COc2ccc([N+](=O)[O-])c3ccccc23)n1
Temperature: -50 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
A mixture of 4-nitronaphthol (741 mg, 3.92 mmol), (2-aminopyrimidin-4-yl)methanol (31) (700 mg, 3.92 mmol) and PPh3 (1233 mg, 4.70 mmol) in THF (20 mL) was cooled to −50° C. under nitrogen and was treated dropwise over 5 min with DIAD (996 μl, 4.70 mmol). After completion of the addition, the mixture was allowed to warm to RT and stirred for 1 hr. A yellow precipitate forms during this time. After stirring overnight, the volatiles were evaporated and the residue triturated from MeOH (50 mL). The pale yellow solid collected by filtration and washed with diethyl ether (50 mL) to give 4-((4-nitronaphthalen-1-yloxy)methyl)pyrimidin-2-amine (32) (1.1 g, 93%): m/z 297 (M+H)+ (ES+).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:11]#[N:12])[CH:3]=1.[F:13][CH:14]([F:17])[CH2:15][OH:16].[H-].[Na+]>>[CH:8]1([C:7]2[C:2]([O:16][CH2:15][CH:14]([F:17])[F:13])=[CH:3][C:4]([C:11]#[N:12])=[N:5][CH:6]=2)[CH2:10][CH2:9]1
Reactant: N#Cc1cc(Cl)c(C2CC2)cn1
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cc(OCC(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 123c, using 4-chloro-5-cyclopropyl-pyridine-2-carbonitrile (example 145b), 2,2-Difluoro-ethanol (CAN 359-13-7) as starting materials and sodium hydride as reagent. The title compound was isolated (508 mg, 81%) as a yellow solid; MS (ESI, m/z): 225.2 (M+H+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[C:22]([NH2:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>ClCCl>[CH2:9]([O:16][C:17]1[C:22]([NH2:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([Br:1])[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c(OCc2ccccc2)ccc(F)c1F
Solvent: ClCCl
Solvent: O
Product: Nc1c(OCc2ccccc2)cc(Br)c(F)c1F

Procedure:
A round bottom flask containing N-bromosuccinimide (0.52 mg, 2.93 mmol), and dichloromethane (5 mL) is stirred in an ice bath. A solution of the 6-benzyloxy-2,3-difluoro-phenylamine (0.69 mg, 2.93 mmol) in 10 mL of dichloromethane is added quickly in one portion. The resulting mixture is stirred for 20 min then water is added and the resulting mixture is extracted twice with DCM. The organic portion is dried over MgSO4, filtered and concentrated to afford the title compound, which is used directly in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:26]1C=C(C)C=CC=1[N+]([O-])=O>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([O:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[CH3:26])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: Cc1ccc([N+](=O)[O-])c(OC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Product: Cc1ccc([N+](=O)[O-])c(O[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 53.6 %

Procedure:
In a similar manner to that described for the preparation of (S)-2-(tert-butoxycarbonylamino)-3-(5-methyl-2-nitrophenoxy)propanoic acid except the reaction mixture was stirred at 0° C. for 4 h, (2S,3S)-2-(tert-butoxycarbonylamino)-3-hydroxybutanoic acid DCHA (2.0 g, 5.00 mmol) and 2-fluoro-4-methyl-1-nitrobenzene (1.55 g, 9.99 mmol) were converted to (2S,3S)-2-tert-butoxycarbonylamino-3-(5-methyl-2-nitro-phenoxy)-butyric acid (0.95 g, 53.6% yield).
Reaction SMILES: [F-].[K+].[Br:3][C:4]1[N:9]=[C:8]([C:10]2([CH3:25])[CH2:12][N@@:11]2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:7]([F:26])=[C:6]([Si](CC)(CC)CC)[CH:5]=1.CC(O)=O.C([O-])(O)=O.[Na+]>C1COCC1.CC(OC)(C)C.CN(C=O)C>[Br:3][C:4]1[N:9]=[C:8]([C:10]2([CH3:25])[CH2:12][N@@:11]2[S:13]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)(=[O:14])=[O:15])[C:7]([F:26])=[CH:6][CH:5]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(C2(C)C[N@@]2S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1F
Agent: CC1(c2nc(Br)ccc2F)C[N@]1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC[Si](CC)(CC)c1cc(Br)nc(C2(C)C[N@]2S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1F
Agent: O=C([O-])O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1(c2nc(Br)ccc2F)C[N@@]1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium fluoride (1.1 g, 18.85 mmol) was added to a solution of 6-bromo-3-fluoro-2-[(S)-2-methyl-1-(4-nitro-benzenesulfonyl)-aziridin-2-yl]-4-triethylsilanyl-pyridine (5 g, 9.43 mmol) and AcOH (1.13 g, 9.43 mmol) in 25 ml THF. DMF (35 ml) was added and the suspension was stirred for 1 h at rt. The reaction mixture was poured onto a mixture of sat. aq. NaHCO3 and TBME. The layers were separated and washed with brine and TBME. The combined organic layers were dried over MgSO4.H2O, filtered and evaporated to give a yellow oil which was crystallized from TBME/hexane to yield 3.45 g of the title compound as white crystals. HPLC: RtH13=2.612 min; ESIMS: 416, 418 [(M+H)+, 1Br]; 1H-NMR (400 MHz, CDCl3): 8.41 (d, 2H), 8.19 (d, 2H), 7.48 (dd, 1H), 7.35 (t, 1H), 3.14 (s, 1H), 3.03 (s, 1H), 2.04 (s, 3H); α[D]-35.7° (c=0.89, DCM).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1>C1COCC1>[OH:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][NH:37][C:2]2[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=3)[N:3]=2)=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Reactant: NCc1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To a suspension of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (10 g, 24.71 mmol) and Hunig's Base (8.63 mL, 49.4 mmol) in THF (100 mL) was added 4-(aminomethyl)phenol (3.19 g, 25.9 mmol). The resulting mixture was refluxed for 1 hour. After cooling to rt, the solvent was removed and the crude product was purified by silica gel chromatography using 20-40-100% EtOAc/Hexanes to give tert-butyl 4-((4-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (10.3 g, 85%) as white solid.
Reaction SMILES: Cl[Si:2]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH2:22]>C(OCC)(=O)C>[OH:22][Si:2]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(CCCC[Si]1(Cl)CCCCC1)OCc1ccccc1
Reactant: O
Solvent: CCOC(C)=O
Product: O=C(CCCC[Si]1(O)CCCCC1)OCc1ccccc1
Yield: 55 %

Procedure:
To crude benzyl 5-(1-chlorosilinan-1-yl)pentanoate (400 mg, 1.23 mmol) 1 N aqueous sodium hydroxide (0.3 mL, 0.3 mmol) was added and the contents sonicated for 10 minutes. After this time, the reaction was diluted with water (1 mL) and sonicated for 5 minutes. After this time, the reaction mixture was diluted further with water (10 mL) and ethyl acetate (25 mL). The organic layer was separated from the aqueous layer, and the aqueous layer was back extracted with ethyl acetate (2×25 mL). The combined organics were dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting with hexanes to 1:4 ethyl acetate/hexanes over 40 minutes to afford benzyl 5-(1-hydroxysilinan-1-yl)pentanoate (209 mg, 55%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.38-7.27 (m, 5H), 5.10 (s, 2H), 2.74 (bs, 1H), 2.39-2.29 (m, 2H), 1.76-1.57 (m, 6H), 1.48-1.30 (m, 4H), 0.72-0.47 (m, 6H).
Reaction SMILES: BrC1C=CC(C([O:8][C@@H:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)[C:12]=3[C@H:11]([CH3:31])[CH2:10]2)=O)=CC=1.O.O.[OH-].[Li+]>C1COCC1>[OH:8][C@@H:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:12]=2[C@H:11]([CH3:31])[CH2:10]1
Reactant: C[C@@H]1C[C@H](OC(=O)c2ccc(Br)cc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
Lithium hydroxide hydrate (0.779 mL, 28.0 mmol) was added to a solution of tert-butyl 4-((5R,7R)-7-(4-bromobenzoyloxy)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (5.8 g, 11.2 mmol) in THF:H2O (150 mL, 2:1) at 0° C. The mixture was allowed to warm to room temperature and stirred at for 1 hour. The mixture was concentrated in vacuo, taken up into saturated sodium bicarbonate (100 mL) and extracted into EtOAc (2×200 mL). The reaction was dried over Na2SO4 and concentrated in vacuo to give tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (3.8 g, 11.4 mmol, 100% yield) as a foam. Similarly, tert-butyl 4-((5R,7S)-7-(4-bromobenzoyloxy)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.29 g, 2.49 mmol) was dissolved in THF:H2O (10 mL, 2:1), cooled to 0° C. and then treated with solid lithium hydroxide hydrate. The solution was stirred at ambient temperature for 16 hours. The reaction was quenched with saturated NH4Cl and concentrated in vacuo. The resulting residue was diluted with ethyl acetate and a small amount of water. The layers were separated, and the aqueous layer was washed with ethyl acetate. The combined organic layers were washed with saturated NaHCO3 (2×), saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The resulting residue was dried under high vacuum to give tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate as a foam (0.843 g, 100%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](Br)=[C:21]([CH3:26])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][N:30]=1.CS(C)=O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:33]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=4)=[C:21]([CH3:26])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Br)c(C)c3)nc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)c4)c(C)c3)nc2)CC1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To the mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-bromo-3-methylphenyl)acetamide 159-1 (65 mg, 0.15 mmol) and 2-methyl-4-(tributylstannyl)pyridine 159-2 (58 mg, 0.15 mmol) in DMF (0.8 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 0.036 mmol). The reaction was stirred at 110° C. for 20 hours. After cooling down to room temperature, the reaction mixture was diluted into DMSO and purified by reverse-phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-methyl-4-(2-methylpyridin-4-yl)phenyl)acetamide 159 as off-white solid. MS m/z 444.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.47 (s, 1H), 8.41 (d, 1H), 7.97 (d, 1H), 7.88 (d, 1H), 7.37 (dd, 1H), 7.21-7.18 (m, 2H), 7.16 (s, 1H), 7.12-7.09 (m, 2H), 3.61 (s, 2H), 3.52 (m, 4H), 3.08 (t, 2H), 3.02 (t, 2H), 2.17 (s, 3H), 1.97 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:11]2[N:12]=[N:13][CH:14]=[CH:15][C:10]=2[CH:9]=1.[F:17][C:18]([F:47])([F:46])[C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:33]=[C:32]([CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)[O:31][N:30]=1>>[F:47][C:18]([F:17])([F:46])[C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:33]=[C:32]([CH2:34][N:13]2[CH:14]=[CH:15][C:10]3=[CH:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:16][C:11]3=[N:12]2)[O:31][N:30]=1
Reactant: Fc1ccccc1-c1cc2ccnnc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCc2cc(-c3ccc(C(F)(F)F)cc3C(F)(F)F)no2)cc1
Product: Fc1ccccc1-c1cc2ccn(Cc3cc(-c4ccc(C(F)(F)F)cc4C(F)(F)F)no3)nc-2n1
Yield: 21.1 %

Procedure:
Prepared analogously to the method described for 2-[5[(4-methoxy-2-trifluoro-methylphenyl)-[1,3,4]thiadiazol-2-ylmethyl]-6-(2-fluorophenyl)-2H-pyrrolo[2,3-c]pyridazine beginning with 6-(2-fluorophenyl)-7H-pyrrolo[2,3-c]pyridazine (50 mg, 0.234 mmol) and toluene-4-sulfonic acid 3-(2,4-bis-trifluoromethylphenyl)-isoxazol-5-ylmethyl ester (164 mg, 0.35 mmol) to produce the titled product (25 mg, 21%). 1H-NMR: (d6-DMSO, 400 MHz) δ 8.73 (d, 1H), 8.40 (dt, 1H), 8.21 (d, 1H), 8.16 (d, 1H), 8.04 (d, 2H), 7.93 (d, 1H), 7.48 (m, 1H), 7.32 (m, 2H), 7.14 (d, 1H), 7.00 (s, 1H), 6.15 (s, 2H). LCMS calculated for C24H13F7N4O 506.10, found 507.07 (M+H)+.