Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[ClH:37]>CCOC(C)=O>[ClH:37].[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:19][NH:18][CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](O[C@H]1CNC[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.5 g (2.876 mmol) tert-butyl (3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidine-1-carboxylate (Step C) in 10 mL EtOAc was added 10 mL of a solution of sat. anhdr. HCl in EtOAc. The reaction mixture was a stirred at RT for 24 hr and the solvent removed under vacuum to afford a yellow oil. The resulting oil was recrystallized from ether/hexanes (3/7) to afford the title compound as a white solid (mp=107° C.). 1H-NMR (CD3OD): δ: 1.43 (d, 3H, 6.5 Hz), 3.27 (t, 1H, 8.5 Hz), 3.44 (m, 2H), 3.73 (m, 2H), 4.20 (q, 1H, 5.5 Hz), 4.78 (q, 1H, 6.5 Hz), 7.01 (t, 2H), 7.20 (dd, 2H), 7.73 (s, 2H), 7.82 (s, 1H)ppm. MS: 422.1 (MH)+ observed.
Reaction SMILES: C1(C(=[N:14][C:15]2[N:20]=[C:19]([CH2:21][C:22]([O-:24])=[O:23])[CH:18]=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[CH2:26]1COCC1.O>>[NH2:14][C:15]1[N:20]=[C:19]([CH2:21][C:22]([O:24][CH3:26])=[O:23])[CH:18]=[CH:17][CH:16]=1
Reactant: C1CCOC1
Reactant: O=C([O-])Cc1cccc(N=C(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: O
Product: COC(=O)Cc1cccc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
{6-[(diphenylmethylidene)amino]pyridin-2-yl}acetate (1.3 g, 3.93 mmol) was dissolved in 1:1 mixture of THF/water (20 mL) and treated with 4.5 mL of a 1N aqueous hydrochloric acid solution. The reaction was allowed to stir at ambient temperature for 30 minutes and then concentrated in vacuo. The crude residue was dissolved in DCM and washed with a saturated aqueous sodium bicarbonate solution. The organic layers were dried over sodium sulfate, filtered and concentrated to afford crude methyl (6-aminopyridin-2-yl)acetate which was used without further purification: LC/MS (M+H)+167.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([NH:19][CH2:20][C:21]4[C:22]([O:28][CH3:29])=[N:23][CH:24]=[C:25]([F:27])[CH:26]=4)=[N:16][C:17]=3[F:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.N1CCC[C@H]1C(O)=O.[CH3:38][S:39]([O-:41])=[O:40].[Na+].[OH-].[Na+]>CS(C)=O.[Cl-].[Na+].O.[Cu]I.C(OCC)(=O)C>[F:18][C:17]1[N:16]=[C:15]([NH:19][CH2:20][C:21]2[C:22]([O:28][CH3:29])=[N:23][CH:24]=[C:25]([F:27])[CH:26]=2)[CH:14]=[CH:13][C:12]=1[CH2:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([S:39]([CH3:38])(=[O:41])=[O:40])[CH:3]=2)[NH:8][CH:9]=1
Reactant: CS(=O)[O-]
Reactant: COc1ncc(F)cc1CNc1ccc(Cc2c[nH]c3ncc(Br)cc23)c(F)n1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Cl-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ncc(F)cc1CNc1ccc(Cc2c[nH]c3ncc(S(C)(=O)=O)cc23)c(F)n1
Temperature: 100 °C

Procedure:
[5-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amine (P-1497, 1 equivalent) is dissolved in 5 mL of dimethyl sulfoxide in a sealable vial. Copper(I) iodide (0.2 equivalent), L-proline (0.2 equivalent), sodium methanesulfinate (175, 1.2 equivalents), and sodium hydroxide (0.2 equivalent) are added. The vial is sealed and heated at 100° C. overnight, then additional copper(I) iodide (0.2 equivalent), L-proline (0.2 equivalent), sodium methanesulfinate (1.2 equivalent), and sodium hydroxide (0.2 equivalent) are added, and the reaction is sealed and heated at 120° C. overnight. The reaction is added to ethyl acetate and brine and extracted. The organic layer is concentrated under vacuum and the resulting material dissolved in tetrahydrofuran for purification on a C18 reverse phase column, eluting with 0-100% methanol (with 10% tetrahydrofuran)/water. Appropriate fractions are combined and concentrated under vacuum. The resulting material is triturated with methyl tert-butyl ether and filtered, washing with methyl tert-butyl ether, then heptane. The solid is dried under vacuum to provide the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].[H-].[Na+].[CH3:25][O:26][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31]Br>CS(C)=O>[CH3:25][O:26][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: COC(=O)CCCCBr
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CCCCOc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1

Procedure:
As described in Example 23, 125 mg (0.43 mmol) off 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (Example 2), 30 mg of 60% NaH/mineral oil and 0.1 mL of 5-bromopentanoic acid methyl ester in 15 mL of DMSO were reacted to give 80 mg of 5-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]pentanoic acid methyl ester, after chromatography on silica (eluted with CH2Cl2 →2% MeOH/CH2Cl2). This material in 5 mL of THF and 15 mL of EtOH was treated with 2 mL of 2N NaOH and the mixture stirred for 18 hours. After acidifying with 5N HCl, the mixture was extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was dissolved in MeOH/CH2Cl2, concentrated and diluted with ether to give 80 mg (100% yield) of 5-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]pentanoic acid, mp, 168°-169° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=2)[CH2:4][O:3]1.[H][H]>O1CCOCC1.[Pd]>[CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=2)[CH2:4][O:3]1
Reactant: COc1ccc([N+](=O)[O-])c(NC2COC(C)(C)OC2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1ccc(N)c(NC2COC(C)(C)OC2)n1

Procedure:
N-(2,2-Dimethyl-1,3-dioxan-5-yl)-6-(methyloxy)-3-nitro-2-pyridinamine (35.00 g, 123.6 mmol) was divided into 2 aliquots, each of which was taken up in 1,4-dioxane (500 ml) and hydrogenated over 10% Pd on carbon (paste, 1:1 w:w with water, 4.00 g) under 1 atm. hydrogen pressure, at room temperature overnight. The mixtures were filtered with suction though Celite, using an argon blanket and taking care to minimise contact of the product with air. The solution was evaporated under reduced pressure to give the title compound as a deep purple oil. This was used immediately in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:15]2[O:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:2].[Br:19]Br>C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:15]2[O:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]=2[CH:10]=[C:9]([Br:19])[CH:8]=1)[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)CCc1cccc2c1OCC2(C)C
Solvent: CCO
Product: CCOC(=O)CCc1cc(Br)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A stirred, cooled (ice bath) solution of 3-(3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-propionic acid ethyl ester (Intermediate 75, 0.71 g, 2.86 mmol) in ethanol (14 mL) was treated with bromine (0.3 mL, 5.819 mmol) and the reaction mixture was allowed to gradually warm up to room temperature over 1.5 h. The volatiles were then evaporated in vacuo and the residue was dissolved in diethyl ether and washed with water (×1), aqueous sodium thiosulfate solution (×1) and brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound as an oil (0.875 g, 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1)([O-:3])=[O:2].C1(N)CCCCC1>C(O)(C)C>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)c([N+](=O)[O-])c1
Solvent: NC1CCCCC1
Solvent: CC(C)O
Product: Cc1ccc(-c2ccc(C(O)CCC(=O)O)cc2)c([N+](=O)[O-])c1
Yield: 68 %

Procedure:
Prepared analogous to Example 25 from 4-(2'-nitro-4'-methyl-4-biphenylyl)-4-oxo-butyric acid. Yield: 68% of theory. Melting point of the cyclohexylamine salt: 156°-157° C. (from isopropanol).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:4]([NH2:18])[S:3]1.[CH3:19]N>CO.O>[CH3:1][CH:2]1[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)=[C:4]([NH:18][CH3:19])[S:3]1
Reactant: CN
Reactant: CC1SC(N)=C(c2cccc(C(F)(F)F)c2)C1=O
Solvent: O
Solvent: CO
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(C)S1

Procedure:
In this example a mixture containing 5.46 g of 2-methyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrothiophene; 6.2 g of methyl amine; 9.30 g of water in 20 ml of methanol was placed in a sealed pressure vessel (steel bomb) and heated for 18 hours at 105° C.; then 18 hours at 120° C.; and then 18 hours at 115° C. The mixture was diluted with water and extracted three times with dichloroethane. The extracts were combined and then washed with water, dried over magnesium sulfate and then evaporated affording the title compound as an impure oil residue which was then purified by chromatography over silica gel eluting with methanol:chloroform.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.[OH:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:19][C:18]1[CH:20]=[CH:21][C:15]([OH:14])=[CH:16][CH:17]=1)[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: Nc1ccc(O)cc1
Product: COc1ccc2c(c1)CCCC2=Nc1ccc(O)cc1
Temperature: 180 °C

Procedure:
A mixture of 6-methoxytetralone (25 g, 142 mmol) and 4-hydroxyaniline (16.3 g, 149 mmol) was heated to 180° C. under a nitrogen stream for 2 h. After cooling to ambient temperature, the solid mass was recrystallized from toluene/methanol: 1NMR (300 MHz) d 8.15 (d, J=9.7 Hz, 1H), 6.5-7.9 (m, 6H), 3.80 (s, 3H), 2.84 (t, J=7.3 Hz, 2H), 2.51 (t, J=6.8 Hz, 2H), 1.85 (m, 2H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]23[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]4)[CH2:19]2)[CH2:25]3)[C:13](=[O:28])[CH2:12]1)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[C:18]12([CH2:17][N:14]3[CH2:15][CH2:16][NH:11][CH2:12][C:13]3=[O:28])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1CC12CC3CC(CC(C3)C1)C2
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNCCN1CC12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h

Procedure:
4-Benzyloxycarbonyl-[1-((adamant-1-yl)methyl)]-piperazin-2-one (300.0 mg, 0.9 mmol), prepared as described in Step 3, was dissolved into neat trifluoroacetic acid(5.0 ml) and the reaction allowed to stir for 30 minutes. Excess trifluoroacetic acid was removed under high vacuum and the resulting gum treated with 4.0N HCl in dioxane and after 10 minutes excess solvents were removed under high vacuum to give 1-((adamant-1-yl)methyl)piperazin-2-one as the hydrochloride salt. 400 Mhz H1 NMR (CD3OD): 1.62(s, 6H),1.68-1.77 (m,6H), 1.97(br s,3H), 3.16(s, 2H), 3.52(t, 2H), 3.72(t,2H), 3.86(s, 2H). High res. FAB MS: Theoretical Mass 249.1961, Measured Mass 249.1952(C15H24N2O+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C:11]1([CH2:14][OH:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C:11]1([CH2:14][O:15][CH3:17])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1(CO)CC1)OCc1ccccc1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC1(NC(=O)OCc2ccccc2)CC1
Reaction time: 5 h
Yield: 42.5 %

Procedure:
To a solution of benzyl[1-(hydroxymethyl)cyclopropyl]carbamate (0.32 g, 0.0014 mol) in methylene chloride (5.0 mL) was added sequentially powdered MS 4A, N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (0.77 g, 0.0036 mol), and trimethyloxonium tetrafluoroborate (0.43 g, 0.0029 mol) at RT. The mixture was stirred for 5 h, filtered through a pad of Celite, and washed with EtOAc. The filtrate was washed with 1N HCl, water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with EtOAc in hexanes (0-30%) to afford the desired product (140 mg, 41%). LCMS: (M+H)=236.1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O>[CH3:1][C:2]1[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
A stirred solution of 2-methyl-5-(trifluoromethyl)benzoic acid (1 mmol) in conc. H2SO4 (2 mL) was cooled to −10° C. and a nitrating mixture (0.4 mL of conc. H2SO4+0.1 mL of conc. HNO3) was added to it in dropwise manner. The reaction mixture was stirred at same temperature for 20 min before warming to room temperature. The resulting precipitate was filtered off and dried to obtain 2-methyl-3-nitro-5-(trifluoromethyl)benzoic acid which was used in next step without further purification (yield 60-70%).
Reaction SMILES: CN(C=O)C.C(N(CC)CC)C.[O:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.[Si:20](Cl)([CH3:23])([CH3:22])[CH3:21]>CCCCC>[O:13]1[CH2:18][CH:17]=[C:16]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14]1
Reactant: O=C1CCOCC1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCCCC
Solvent: CN(C)C=O
Product: C[Si](C)(C)OC1=CCOCC1
Temperature: 140 °C
Yield: 58.1 %

Procedure:
To a flame-dried sealed tube was added DMF (3 ml) and triethylamine (3.34 ml, 23.97 mmol), followed by tetrahydro-4H-pyran-4-one (0.923 ml, 9.99 mmol) and TMS-Cl (1.532 ml, 11.99 mmol). The mixture was heated at 140° C. for 16 hours, allowed to cool to room temperature, diluted with pentane and decanted into ice cooled saturated sodium bicarbonate and extracted with pentane (50 ml×3). The combined pentane layers were washed with brine and dried over sodium sulfate, filtered and concentrated to give 1.0 g of the product as a liquid (5.80 mmol, yield 58.1%). 1H NMR (400 MHz, CDCl3) δ (ppm) 4.63-4.61 (m, 1H), 3.95-3.93 (m, 2H), 3.60-3.58 (m, 2H), 1.94-1.90 (m, 2H), 0.01 (b, 9H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:31])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]3[CH:24]=[CH:25][N:26]=[C:27]([C:28](O)=[O:29])[C:22]3=[N:21][N:20]=2)=[CH:15][CH:14]=1.C([O:38][C:39](=[O:45])[C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1)(C)(C)C>>[F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:31])[NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]3[CH:24]=[CH:25][N:26]=[C:27]([C:28]([N:41]4[CH2:42][CH2:43][CH2:44][C@H:40]4[C:39]([OH:45])=[O:38])=[O:29])[C:22]3=[N:21][N:20]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(Nc1ccc(-c2nnc3c(C(=O)O)nccn23)cc1)Nc1ccccc1OC(F)(F)F
Product: O=C(Nc1ccc(-c2nnc3c(C(=O)N4CCC[C@H]4C(=O)O)nccn23)cc1)Nc1ccccc1OC(F)(F)F

Procedure:
The title compound was prepared from 3-(4-(3-(2-(trifluoromethoxy)phenyl)ureido)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine-8-carboxylic acid (61G) and L-proline tert-butyl ester by analogous procedure described in Example 61H. HPLC/MS (Method C): retention time=1.91-2.01 min (broad rotomer), [M+H]+=556.4.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13](CC4C=CC(OC)=CC=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:8]=23)=[C:4]([F:35])[CH:3]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49](O)=[O:50])[C:44]2=[O:52])=[CH:39][CH:38]=1.O=C1C(C(OC)=O)=CC=CO1.FC1C=CC(N)=CC=1>>[F:35][C:4]1[CH:3]=[C:2]([NH:1][C:49]([C:45]2[C:44](=[O:52])[N:43]([C:40]3[CH:39]=[CH:38][C:37]([F:36])=[CH:42][CH:41]=3)[CH:48]=[CH:47][CH:46]=2)=[O:50])[CH:34]=[CH:33][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[C:15]([NH:16][CH:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[C:8]=12
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: COC(=O)c1cccoc1=O
Agent: Nc1ccc(F)cc1
Product: CN1CCC(Nc2n[nH]c3nccc(Oc4ccc(NC(=O)c5cccn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Yield: 73 %

Procedure:
Prepared by a 2-step process from 4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (prepared in Example 101, step A) and 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (prepared from methyl 2-oxo-2H-pyran-3-carboxylate with 4-fluoroaniline and followed by hydrolysis using the methods described in US Publication No. 2005/0239820) according to the procedure of Example 101. The crude was rinsed with Et2O to afford 14 mg (73%) of the desired product. LRMS (ESI pos) m/e 572.0 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.72 (d, 1H), 8.24 (d, 1H), 8.02 (dd, 1H), 8.02 (dd, 1H), 7.87 (d, 1H), 7.47 (m, 2H), 7.41 (m, 1H), 7.38 (m, 3H), 6.72 (m, 1H), 6.12 (d, 1H), 3.70 (m, 1H), 2.88 (d, 2H), 2.35 (s, 3H), 2.24 (m, 1H), 2.21 (m, 2H), 1.62 (m, 2H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −112.6, −128.0.
Reaction SMILES: [C:1]12([NH:6][C:7](=[O:9])[CH3:8])[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[OH:10]S(O)(=O)=O.O(C(C(F)(F)F)=O)C(C(F)(F)F)=O.N([O-])=O.[Na+].C(O)(C(F)(F)F)=O.O=O.O(OC)OC.C(OO)(=O)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.S(O)(C(F)(F)F)(=O)=O>C(Cl)Cl.CC(O)=O>[OH:10][C:3]12[CH2:5][C:1]([NH:6][C:7](=[O:9])[CH3:8])([CH2:4]1)[CH2:2]2
Reactant: O=S(=O)(O)O
Reactant: CC(=O)NC12CC(C1)C2
Agent: CC(=O)OO
Agent: COOOC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC12CC(O)(C1)C2

Procedure:
The C—H activation/oxidation (Scheme 4) of commercially available bicyclo[1.1.1]pentan-1-amine by an appropriate oxidizing reagent or condition (for example, H2SO4 (conc.)/HNO3 (conc. or 50%); H2SO4 (conc.)/NH4NO3; perfluoro-cis-2-n-butyl-3-n-propyloxaziridine; CBr4/H2O/Mo(CO)6; [(Me3tacn)RuCl3], CAN, AgClO4, t-BuOH/H2O; RuCl3-xH2O, KBrO3, H2O, pyridine, CH3CN; dimethyldioxirane (DMD) or methyl(trifluoromethyl)dioxirane (TFDO), with or without HBF4; CrO3, H5IO6; KMnO4, KOH; and the like) can give 3-aminobicyclo[1.1.1]pentan-1-ol. The amino alcohol intermediate can then be coupled with an appropriate carboxylic acid or acid chloride, such as acetyl chloride to give 3-acetamidobicyclo[1.1.1]pentan-1-yl acetate (3). Selective hydrolysis of the ester group with hydroxide ion gives N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1). Alternatively, starting with N-(bicyclo[1.1.1]pentan-1-yl)acetamide (4), C—H activation/oxidation with an appropriate oxidizing reagent or conditions (for example, see listed above, and H2SO4 (conc.), (CF3CO)2O; NaNO2, TFA, O2; CrO3, CH3CO2H, (H3CO)2O; RuCl3 (cat.), TFA, DCM, peracetic acid; DDQ, TfOH; and the like) can give N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]([CH:11]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].Br[CH2:32][C:33](=[O:44])/[CH:34]=[CH:35]/[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=1.BrCC(OCC)=O>C1(C)C=CC=CC=1>[CH3:43][O:42][C:38]1[CH:37]=[C:36](/[CH:35]=[CH:34]/[C:33](=[O:44])/[CH:32]=[CH:11]/[C:9]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:10])[CH:41]=[CH:40][CH:39]=1
Reactant: COc1cccc(/C=C/C(=O)CBr)c1
Reactant: COCCOCCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)CBr
Solvent: Cc1ccccc1
Product: COCCOCCOC(=O)/C=C/C(=O)/C=C/c1cccc(OC)c1

Procedure:
A solution of 14.9 g (35.2 mmol) of [[[2-(2-methoxyethoxy)ethoxy]carbonyl]methylene]triphenylphosphorane (preparation see paragraph (c)) in 100 ml of toluene was treated with 4.48 g (17.6 mmol) of (E)-1-bromo-4-(3-methoxyphenyl)-3-buten-2-one (preparation see paragraph d)). The reaction mixture was stirred at reflux for 2 hours and then filtered. After the addition of 1.63 ml (17.6 mmol) of ethyl bromoacetate, the filtrate was again stirred at reflux for 2 hours. The separated solid was filtered off. The filtrate was concentrated and purified by flash chromatography on 500 g of silica gel (elution agent ether/hexane 10:1). Crystallization of the purified product from methylene chloride/ether/hexane yielded 2-(2-methoxyethoxy)ethyl (E,E)-6-(3-methoxyphenyl)-4-oxo-2,5-hexadienoate of melting point 59°-60°.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)=[C:8]([C:24](=[O:26])[NH2:25])[CH:7]=[N:6][N:5]2[CH:27]=1.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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(Cl)Cl.O1CCOCC1>[C:24]([C:8]1[CH:7]=[N:6][N:5]2[CH:27]=[C:2]([C:32]3[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=3)[N:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)(=[O:26])[NH2:25]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)nc12
Temperature: 90 °C

Procedure:
To a reaction vial charged with (3S,4S)-tert-butyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-methylpyrrolidine-1-carboxylate (from Step 3 of Example 1, 300 mg, 0.683 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (426 mg, 2.049 mmol) and PdCl2(dppf)-CH2Cl2 Adduct (55.8 mg, 0.068 mmol) were added dioxane (4.553 ml) and potassium phosphate, tribasic (1024 μl, 2.049 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 90° C. for 1 hr. The reaction mixture was diluted with methanol (10 ml), filtered, and concentrated under reduced pressure, yielding a dark oil. The oil was partitioned between ethyl acetate and water. The organic layer was washed with (sat.) sodium chloride, dried with sodium sulfate, filtered and concentrated under reduced pressure to give an oil. The crude oil was purified via flash chromatography (ISCO silica gel column, 0-10% DCM-MeOH eluents) to give (3S,4S)-tert-butyl 3-((7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)amino)-4-methylpyrrolidine-1-carboxylate as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ 8.33 (s, 1H), 8.03-7.95 (m, 2H), 7.86 (s, 1H), 6.07-5.86 (m, 1H), 3.93 (s, 3H), 3.85-3.73 (m, 1H), 3.72-3.62 (m, 1H), 3.57-3.45 (m, 1H), 3.23-3.14 (m, 1H), 2.67 (d, J=4.8 Hz, 1H), 1.46 (d, J=13.0 Hz, 9H), 1.16-1.06 (m, 3H). ESI-MS (analytical LCMS Method B): m/z 441.3 ([M+H]+). HPLC (analytical HPLC Method B) Rt: 3.123 min.