Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH2:25].Cl>O1CCCC1>[OH:25][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:2]=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=O)cc2)cc1
Reactant: O
Agent: Cl
Agent: [K]
Solvent: C1CCOC1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccccc3O)cc2)cc1
Reaction time: 2 h
Yield: 72 %

Procedure:
In a reaction container equipped with a stirring device, a thermometer and a tap funnel, 14.8 g of potassium tert-buthoxide and 50 ml of tetrahydrofuran are replaced. In nitrogen airstream, a solution in which 9.90 g of 2-hydroxy benzyl diethyl phosphonate and 5.44 g of 4-(N,N-bis(4-methylphenyl)amino)benzaldehyde are dissolved in tetrahydrofuran is slowly dropped to the reaction container at room temperature and the reaction is conducted for 2 hours. Next, while cooled down by water, water is added to the resultant and thereafter 2N hydrochloric acid is added to acidify the resultant. Furthermore, tetrahydrofuran is removed by an evaporator and the obtained coarse product is extracted by toluene. The toluene phase is washed with water, sodium hydrogen carbonate aqueous solution and saturated salt solution in this order. Magnesium sulfide is added to the resultant for dehydration. Subsequent to filtration, toluene is removed and an oily coarse product is obtained. Subsequent to column refinement by silica gel, the resultant is crystallized in hexane and 5.09 g (yield ratio: 72%) of 2-hydroxy-4′-(N,N-bis(4-methylphenyl)amino)stilbene is obtained. The melting point of the product is 136.0 to 138.0° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([F:13])[CH:6]=1)(=O)C.[N+]([O-])(O)=O>C(O)(=O)C.C(OC(=O)C)(=O)C>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([F:13])[CH:6]=1
Reactant: COc1ccc(NC(C)=O)cc1F
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 1114.4 %

Procedure:
To a cold (15°), stirred solution of 12.8 g (0.0699 mol) of 4-acetamido-2-fluoroanisole in 55 mL of acetic acid and 27 mL of acetic anhydride was added, dropwise, 6.5 g (0.072 mol) of 70% nitric acid (sp. gr. 1.424) at such a rate that the temperature of the reaction mixture did not exceed 16°. The solution was stirred for 1.5 hours at room temperature then poured into 400 mL of ice-water. The aqueous suspension was extracted with methylene chloride (1×300 mL; 1×200 mL), then the combined extracts were concentrated in vacuo to a solid (13 g). The material was chromatographed on a column of silica gel (300 g) using benzene as the eluent. The fractions containing the required product were combined then concentrated in vacuo. The solid residue was dissolved in methylene chloride (400 mL) and the solution was washed with water, dried over anhydrous magnesium sulfate, then concentrated in vacuo; yield, 10.0 g (62.9%). The material was suitable for further transformation. Additional material (169 g; 44.6%) was obtained from 110 g (0.779 mol) of 4-amino-2-fluoroanisole without isolating the intermediate 4-acetamido-2-fluoroanisole (3).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]2=[N:11][C:10]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])C1C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH:18]=[C:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:12]2=[N:11][C:10]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC=C2c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCC=C2c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
A solution of intermediate 16, ethyl 3-(benzyloxy)-4-oxo-9-phenyl-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate (0.320 g, 0.80 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (5 ml) and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated in vacuo and the residue was triturated with ether to give 0.189 g (76% yield) of the title material as a white solid; mp 151° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.37 (3H, t, J=7.1 Hz, CH3), 2.67 (2H, m, CH2), 4.34 (2H, t, J=7.1 Hz, CH2), 4.37 (2H, q, J=7.1 Hz, OCH2), 6.70 (1H, t, J=4.8 Hz, CH), 7.38 (3H, m, aromatics), 7.55 (2H, m, aromatics), 10.70 (1H, s, OH). HRMS (ESI+) calculated for C17H17N2O4 [M+H+]: 313.1188; found: 313.1181.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25](Cl)=O>O1CCCC1>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25]1[O:4][CH2:3][CH:2]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:6]=2)[N:1]=1
Reactant: CC(C)(C)c1ccc(C(N)CO)cc1
Reactant: O=C(Cl)c1c(F)cccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2COC(c3c(F)cccc3Cl)=N2)cc1
Temperature: 60 °C

Procedure:
A 100 ml eggplant-shaped flask was charged with 1.4 g (7.25 millimoles) of 2-amino-2-(4-t-butylphenyl)-1-ethanol and 0.73 g (7.25 millimoles) of triethylamine and 30 ml of tetrahydrofuran, and a solution of 1.4 g (7.25 millimoles) of 2-chloro-6-fluorobenzoyl chloride in 10 ml of tetrahydrofuran was added over 30 minutes to the flask with ice cooling and stirring. The mixture was stirred further for 3 hours at room temperature. The resulting triethylamine hydrochloride was removed by a glass filter, and the filtrate was concentrated under reduced pressure. The concentrate, thionylchloride (2.6 g; 21.8 and 50 ml of benzene were put in a 200 ml egg-plant-shaped flask, and refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure. Fifty milliliters of methanol was added to the remaining oil, and the mixture was heated to 60° C. To the mixture was added dropwise 5 ml of a 15 % aqueous solution of sodium hydroxide. After the addition, the mixture was stirred at the same temperature for 1 hour, transferred into water, and extracted with ethyl acetate. The extract was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate=8/2) to give 2-(2-chloro-6-fluorophenyl)-4-(4-t-butylphenyl)-2-oxazoline (compound No. 45) as a colorless oil. Yield 1.8 g (74.9 %).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]([NH:9][S:10]([CH:13]([CH3:25])[CH2:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH3:17])(=[O:12])=[O:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][Cl:35]>CC(C)=O>[C:1]([O:5][CH2:6][C:7]([NH:9][S:10]([CH:13]([CH3:25])[CH2:14][CH2:15][CH:16]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:33][CH2:34][Cl:35])=[CH:22][CH:23]=1)[CH3:17])(=[O:12])=[O:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCCBr
Reactant: CC(CCC(C)S(=O)(=O)NC(=O)COC(C)(C)C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(CCC(C)S(=O)(=O)NC(=O)COC(C)(C)C)c1ccc(OCCCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.9 %

Procedure:
To a stirred mixture of N-tertbutoxyacetyl-2-(4-hydroxyphenyl)propyl-2-propanesulfonamide (4.0 g, 11.2 mmol) in acetone (40 mL) was added potassium carbonate (4.64 g, 33.6 mmol) under nitrogen. The resulting mixture was stirred 30 minutes at ambient temperature. Next, 1-bromo-2-chloroethane (1.12 ml, 13.4 mmol) was added and the resulting mixture was heated to reflux while stirring for 48 h. The resulting mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with water (2×50 mL) and brine (1×50 mL), dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo followed by chromatography on silica gel eluting with ethyl acetate-hexane gave 1.5 g (32%) of the pure title compound.
Reaction SMILES: CN(C=[O:5])C.O.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26])[CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>CN(C=O)C.[Pd](Cl)Cl.[Cu]Cl>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][CH2:22][CH2:23][CH2:24][C:25](=[O:5])[CH3:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)C=O
Reactant: C=CCCCOc1cccc(OCc2ccccc2)c1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: Cl
Solvent: O
Product: CC(=O)CCCOc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Palladium(II) chloride (112 mg) and copper(I) chloride (628 mg) were added to DMF-water (7:1, 8 mL), followed by stirring at room temperature under oxygen atmosphere for 1 hour. A solution of 1-(benzyloxy)-3-(pent-4-en-1-yloxy)benzene (1.70 g) in DMF (7 mL) was added dropwise to the reaction mixture, followed by vigorous stirring at room temperature for 2 hours. 0.5M Hydrochloric acid (60 mL) was added to the reaction mixture, followed by extraction with diethyl ether (100 mL). The organic layer was washed sequentially with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain 5-[3-(benzyloxy)phenoxy]pentan-2-one (1.65 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[C:9](OS(C(F)(F)F)(=O)=O)[C:7]=2[N:8]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.ClCCl>O1CCOCC1.Cl[Pd]Cl>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:9]2[C:7]3[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=3[S:11][C:10]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:27][CH:26]=1
Reactant: COC(=O)c1sc2cnc(SC)nc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1sc2cnc(SC)nc2c1-c1ccc(F)cc1
Temperature: 120 °C
Yield: 78.4 %

Procedure:
A mixture of 200 mg of methyl 2-(methylsulfanyl)-7-{[(trifluoromethyl)sulfonyl]oxy}thieno[3,2-d]pyrimidine-6-carboxylate 4 (example 1), 216 mg of 4-fluorophenylboronic acid, 19 mg of dichloropalladium (dppf) and 322 mg of BTPP in 2.5 ml of dioxane under argon is microwave-heated at 120° C. in a sealed tube for 1 h. The medium is taken up with dichloromethane and filtered. The organic phase is washed three times with water, then dried over magnesium sulfate, filtered, and then concentrated under vacuum so as to give a yellow solid. The crude is purified on 80 g of silica, elution being carried out with 0-20% of methanol in dichloromethane, so as to obtain 135 mg of methyl 7-(4-fluorophenyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylate in the form of a yellow solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14].[K]>CN(C)C=O>[C:2]1([CH2:1][O:15][C:13](=[O:14])[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][OH:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(CCO)C(=O)O
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A mixture of benzyl bromide (37.4 g) and 4-hydroxy-2,2-dimethylbutanoic acid, monopotassium salt, (3.4 g) in dimethylformamide (35 mL) was stirred at room temperature for 18 hours. The precipitate was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel eluting with 2:1 dichloromethane:ethyl acetate to give 3.95 g (89%) of 4-hydroxy-2,2-dimethylbutanoic acid phenylmethyl ester as a colorless oil. A sample was evaporatively distilled to give the analytical sample: bp 160°-165° C./0.25 mm; IR (CHCl3) 3595 (OH), 1707 (C=O) and 687 cm-1 (C6H5); NMR (CDCl3) δ 1.23 (s, 6, CH3), 1.85 (t, 2, CH2), 3.67 (t, 2, CH2), 5.11 (s, 2, CH2) and 7.34 (s, 5, Ph); MS m/e 222,91.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.I[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][NH:46]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.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]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32]([C:50]3[N:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(ncn4-c4cccc(NS(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Reactant: IN1C=CC=CN1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cccnn5)cc4)nc32)c1

Procedure:
A solution of N-(3-{1-(4-chloro-phenyl)-6-oxo-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,6-dihydro-purin-9-yl}-phenyl)-methanesulfonamide (prepared as described in example 26, 0.500 g, 0.809 mmol) in N,N-dimethylformamide (20 mL) is degassed with argon for 0.5 h. Then 2-iodopyridazine (0.250 g, 1.21 mmol), cesium carbonate (0.527 g, 1.61 mmol), Pd(dppf)2Cl2 (0.059 g, 0.08 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is heated to reflux for 3 h. The reaction mixture is poured into with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to afford N-{3-[1-(4-chloro-phenyl)-6-oxo-2-(4-pyridazin-3-yl-phenyl)-1,6-dihydro-purin-9-yl]-phenyl}-methane sulfonamide. 1H NMR (DMSO-d6, 400 MHz) δ 10.2 (br, 1H), 9.20 (m, 1H), 8.62 (m, 1H), 8.21 (d, 1H), 8.06 (m, 2H), 7.77 (m, 2H), 7.42-7.57 (m, 8H), 7.25 (d, 1H), 3.05 (s, 3H); LC-MS calculated for C28H20ClN7O3S (M+H+) 570.1, found 570.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:23]=[C:22]([CH2:24][N:25]([CH3:36])[S:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:21]=[CH:20][C:10]=2[O:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:23]=[C:22]([CH2:24][N:25]([CH3:36])[S:26]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)(=[O:28])=[O:27])[CH:21]=[CH:20][C:10]=2[O:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(-c2cccc(C#N)c2)c1)S(=O)(=O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccc(OCC(=O)O)c(-c2cccc(C#N)c2)c1)S(=O)(=O)c1ccc(F)cc1
Yield: 43.6 %

Procedure:
t-butyl 2-(2-(3-cyanophenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (4) (780 mg; 1.53 mmol) was stirred in a mixture of TFA (15 mL) and DCM (30 mL) for 1 h. After concentration in vacuo, the residue was purified via reversed phase semi-preparative HPLC to yield 303 mg (43.6%) of 2-(2-(3-cyanophenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetic acid (Example 5) as a white solid. 1HNMR (CDCl3, 300 MHz): δ 7.84 (m, 3H), 7.75 (m, 1H), 7.61 (m, 1H), 7.50 (t, 1H), 7.24 (m, 3H), 6.85 (d, 1H), 4.69 (s, 2H), 4.13 (s, 2H), 2.63 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[C:8]([CH3:11])[CH:9]=2)[CH:4]=[CH:3]1.P(Cl)(Cl)(OP(Cl)(Cl)=O)=O.CN([CH:25]=[O:26])C>>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([CH:25]=[O:26])=[CH:3]1
Reactant: Cc1cc(C)c2ccn(C)c2c1
Reactant: CN(C)C=O
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Product: Cc1cc(C)c2c(C=O)cn(C)c2c1
Temperature: 25 °C

Procedure:
A solution of 1,4,6-trimethyl-1H-indole (800 mg, 5 mmol) in DMF (0.9 mL) was cooled to 5° C. under nitrogen. The pyrophosphoryl chloride (1.4 mL, 10 mmol) was then slowly introduced. Upon complete addition the cooling bath was removed and the reaction was allowed to warm to ambient temperature. After a total of 45 minutes the reaction was cooled to 5° C. and slowly quenched with 2N NaOH. The pH was adjusted to 8. The solid that precipitate out from the solution was collected by filtration and was washed with water. The remaining white solid was dried in the oven and was confirmed to be the title compound (875 mg, 93%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ON1C2C=[CH:54][CH:55]=[CH:56][C:51]=2[N:50]=N1.C(N(C(C)C)CC)(C)C.N1CCCC1>CN(C)C=O>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:50]4[CH2:51][CH2:56][CH2:55][CH2:54]4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCC2)CC1
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a suspension of {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid (75.0 mg, 0.112 mmole) in dimethylformamide (6 mL) were added successively 1-hydroxybenzotriazole (23.0 mg, 0.169 mmole, Chem-Impex), N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate (64.0 mg, 0.169 mmole, Aldrich) and diisopropylethylamine (58 mg, 0.448 mmole). The mixture was stirred for 15 min before pyrrolidine (12.0 mg, 0.169 mmole, Aldrich) was added. The reaction mixture was allowed to stir for 2 h before concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1 N sodium hydroxide, brine, dried and concentrated. The crude residue was purified by flash column chromatography (silica gel, eluting with a gradient of 1-10% methanol in methylene chloride) to give the title compound (71.8 mg, 89% yield). HR-MS (ES, m/z) calculated for C40H50Cl2N5O3 [(M+H)+] 718.3285, observed 718.328.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][Si:10]([CH3:61])([CH3:60])[CH2:11][CH2:12][O:13][CH2:14][N:15]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:30]=3)=[C:20]2[N:19]=[C:18]([N:37]2[CH2:43][CH:42]3[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH:39]([CH2:40][CH2:41]3)[CH2:38]2)[CH:17]=1>CN(C=O)C.O>[CH3:59][Si:56]([CH3:58])([CH3:57])[CH2:55][CH2:54][O:53][CH2:52][N:15]([CH2:14][O:13][CH2:12][CH2:11][Si:10]([CH3:9])([CH3:60])[CH3:61])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:29][CH:30]=3)=[C:20]2[N:19]=[C:18]([N:37]2[CH2:38][CH:39]3[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH:42]([CH2:41][CH2:40]3)[CH2:43]2)[C:17]=1[Br:8]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NBS (64 mg, 0.36 mmol) was added to a solution of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (249 mg, 0.33 mmol) in DMF (6 mL). After stirring at room temperature for 1 h, the mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: LCMS tR=3.66 Min (5 min run, UV254nm). Mass calculated for M+H 836.3, observed m/z 836.06 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([OH:14])[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.Cl.[NH:45]1[CH2:48][CH:47]([N:49]2[CH2:52][CH:51]([NH:53][C:54](=[O:57])[CH:55]=[CH2:56])[CH2:50]2)[CH2:46]1>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:45]2[CH2:46][CH:47]([N:49]3[CH2:52][CH:51]([NH:53][C:54](=[O:57])[CH:55]=[CH2:56])[CH2:50]3)[CH2:48]2)=[O:13])=[C:4]([OH:14])[CH:3]=1
Reactant: C=CC(=O)NC1CN(C2CNC2)C1
Reactant: O=C(O)CNc1cc(Cl)c(Cl)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(=O)NC1CN(C2CN(C(=O)CNc3cc(Cl)c(Cl)cc3O)C2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 2.9 %

Procedure:
A mixture of 2-(4,5-dichloro-2-hydroxyphenylamino)acetic acid (120 mg, 0.51 mmol), EDCI.HCl (147 mg, 0.77 mmol), HOBt (83 mg, 0.61 mmol), Et3N (154 mg, 1.53 mmol) in DMF (20 mL) was stirred at room temperature for 5 min and then N-(1-(azetidin-3-yl)azetidin-3-yl)acrylamide hydrochloride (150 mg, 0.69 mmol) was added. The resulting mixture was stirred at room temperature for 15 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH/NH3.H2O=100:10:1.5) to afford the desired product (6 mg, 3% yield). 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 8.59 (d, J=8.0 Hz, 1H), 6.79 (s, 1H), 6.55 (s, 1H), 6.20 (dd, J=10.0, 16.8 Hz, 1H), 6.09 (dd, J=2.0, 16.8 Hz, 1H), 5.62 (dd, J=2.0, 9.6 Hz, 1H), 5.20 (t, J=4.0 Hz, 1H), 4.40-4.35 (m, 1H), 4.19-4.15 (m, 1H), 3.96-3.88 (m, 2H), 3.73-3.69 (m, 3H), 3.53-3.45 (m, 3H), 3.00-2.96 (m, 2H). ESI-MS m/z: 399.2[M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:12]1(=O)[O:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=C(C)C=C(C)C=1>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([N:6]2[CH2:12][CH2:13][CH2:14][C:15]2=[O:16])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C1CCCO1
Solvent: O
Solvent: Cc1cc(C)cc(C)c1
Product: O=C1CCCN1c1cccc(C(F)(F)F)c1
Temperature: 198 °C
Yield: 45.8 %

Procedure:
A reaction flask was charged with 70.0 g (0.434 mole) of m-trifluoromethylaniline and 37.4 g (0.434 mole) of butyrolactone. The mixture was heated to reflux at 198° C for 185 minutes. Then, 1.0 g (0.0058 mole) of ptoluenesulphonic acid was added, and the resulting mixture was refluxed for an additional 100 minutes, during which time the temperature dropped from 164° C to 138° C. The mixture was then cooled, a DEan-Stark trap was installed on the condenser, and 50 ml of mesitylene was added. The mixture was then refluxed at 181-187° C until water was no longer produced. The precipitate formed by the reaction was filtered out of the mixture and dried in vacuo, yielding 45.6 g of 1-(m-trifluoromethylphenyl)-2-pyrrolidone, melting point 65°-66° C.