Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([C:22]#[C:23][Si](C)(C)C)[CH:19]=[C:18]([CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:16]2[CH:17]=[C:18]([CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)[CH:19]=[C:20]([C:22]#[CH:23])[CH:21]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C#C[Si](C)(C)C)cc(CN2CCCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(CN2CCCC2)cc(C(Nc2ccc(C#N)cc2)C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.6 %

Procedure:
130 mg of the ethyl (RS)-(4-cyano-phenylamino)-(3-pyrrolidin-1-ylmethyl-5-trimethylsilanylethynyl-phenyl)-acetate described in Example 156.4 were dissolved in 2 ml of THF and treated at 0° C. with 0.43 ml of a 1 molar solution of tetrabutylammonium fluoride in THF. After 5 hrs. at 0° C. water was added to the reaction mixture and an intermediate was extracted with ethyl acetate. This intermediate was treated at 0° C. in 5 ml of MeOH with 31 mg of sodium cyanoborohydride. Then, the pH was adjusted to 6 with methanolic HCl and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then made basic with methanolic KHCO3 and, after removal of the solvent in a vacuum, the residue was purified by column chromatography (CH2Cl2/methanol). There were obtained 27 mg of ethyl (RS)-(4-cyano-phenylamino)-(3-ethynyl-5-pyrrolidin-1-ylmethyl-phenyl)-acetate as a light yellow solid; MS: 374 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccccc1C1CC(C)(C)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and ethanesulfonyl chloride (45 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give ethanesulfonic acid [2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide LC/MS m/e obsd. (ESI+) [(M+H)+] 379.20.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCO[C:24]([CH3:26])=[O:25]>[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:24](=[O:25])[C:26]2[CH:12]=[CH:13][CH:14]=[CH:15][N:18]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cc2ccccc2Cl)cc1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: O=C(Nc1ccc(S(=O)(=O)Cc2ccccc2Cl)cc1)c1ccccn1
Reaction time: 12 h

Procedure:
To a solution of 2-chlorobenzyl)(4-nitrophenyl)sulfane (1.0 equivalent) in DCM at 0° C. was added m-CPBA (3.0 equivalents). After 30 min, the ice bath was removed. The reaction was followed by thin liquid chromatography (TLC). The reaction was added to DCM:NaHCO3 (sat'd) (1:1) and the organic layer was separated. After washing the organic layer with water (2×) and brine, it was dried (MgSO4), filtered and concentrated to provide 1-chloro-2-(((4-nitrophenyl)sulfonyl)methyl)benzene. Analytical: Rf=0.72 (50% EtOAc/hexanes); LCMS (Method 2): RT=1.41 min, >90% @ 254 nM, m/z=333.8 [M+Na]+. Step 3: To a solution of 1-chloro-2-(((4-nitrophenyl)sulfonyl)methyl)benzene in EtOAc (0.3 M) was added 5% Pd/C (˜0.1 equivalent). An H2 atmosphere (1 atm) was applied to the rxn mixture. After 12 h, TLC confirmed loss of starting material, so rxn was filtered through Celite and concentrated. The crude residue, 4-(((2-chlorobenzyl)sulfonyl)aniline, was carried through without further purification (85-95% yield over 2 steps). Analytical: Rf=0.40 (50% EtOAc/hexanes); LCMS (Method 2): RT=1.25 min, >98% @ 254 nM, m/z=281.9 [M+H]+. Step 4: To a solution of the 4-(((2-chlorobenzyl)sulfonyl)aniline in DMF:DIEA (4:1) (0.1 M). The appropriate acid chloride (1.0 equivalent) was added and after 12 h at 85° C., N-(4-(((2-chlorobenzyl)sulfonyl)phenyl)picolinamide was directly purified by mass-guided preparative HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2Br)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1B(O)O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:28]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=3[O:26][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2ccccc2Br)c1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)c1
Yield: 47.4 %

Procedure:
2′-Bromo-biphenyl-3-carboxylic acid ethyl ester (157 mg, 0.5 mmol), 2-benzyloxy-5-chloro-phenylboronic acid (157 mg, 0.6 mmol), tetrakis(triphenylphosphine)palladium(0) (66 mg, 0.06 mmol) and potassium carbonate (568 mg, 4.1 mmol) was heated in toluene-ethanol (1:1, 5 ml) at 90° C. for 4.5 hours. Upon cooling, the mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography using Biotage with iso-hexane containing a gradient of ethyl acetate (1-5%) to yield the title compound (105 mg, 46%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[N:27]3[CH2:32][CH2:31][CH:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O1CCCC1.CO.[OH-].[Li+:46]>O>[Li+:46].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[N:27]3[CH2:32][CH2:31][CH:30]([C:33]([O-:35])=[O:34])[CH2:29][CH2:28]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCN(c2nccc3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N5CCC(C(=O)[O-])CC5)nccc34)no2)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
A mixture of ethyl 1-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]-4-piperidinecarboxylate (D14; 35 mg, 0.067 mmol), tetrahydrofuran (THF) (2.0 ml), methanol (2.0 ml), water (1 ml) and lithium hydroxide (1.61 mg, 0.067 mmol) was left to stir at 80° C. for 3 h. The solvent was removed in vacuo and the residue was triturated with diethyl ether. The mixture was filtered to give the title compound as a pale peach coloured solid (20 mg).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][C@@H:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]1)=[O:19])C1C=CC=CC=1>[Pd].CO>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][C@@H:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Reaction time: 3 h

Procedure:
Palladium on carbon (9.18 mg; 10% Pd/C) was added to a solution of tert-butyl (3R)-3-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)pyrrolidine-1-carboxylate (38 mg, 0.085 mmol) in methanol (2 mL) and the resulting mixture was stirred under hydrogen (balloon) for 3 hours. TLC analysis showed the reaction was complete. The reaction mixture was filtered through a microfilter and the filtrate was concentrated under vacuum to afford the impure title compound as an oil.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16](O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C.C1C=CC(P([N:81]=[N+:82]=[N-:83])(C2C=CC=CC=2)=O)=CC=1>C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>[N:81]([C@@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:35]([O:37][CH3:38])=[O:36])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:21]2[C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:25][C:19]=2[O:18][CH2:17]1)=[N+:82]=[N-:83]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)COc1cc(OCc2ccccn2)ccc1-3
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N=[N+]=[N-])COc1cc(OCc2ccccn2)ccc1-3
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Methyl (7S)-14-cyclohexyl-7-hydroxy-3-(pyridin-2-ylmethoxy)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate was dissolved in THF (60 mM) and PPh3 (1.2 eq) was added. The solution was cooled to 0° C. and treated with DIPEA (1 eq), followed by slow addition of DIAD (1.2 eq). The mixture was left stirring at this temperature for 5 min, then a solution of DPPA in THF (1.2 eq) was added dropwise. After complete addition the mixture was stirred at 0° C. for further 30 min, then stirring was continued at RT. Since no reaction was observed after 1 h more PPh3 in THF (1.2 eq), DIAD in THF (1.2 eq) and DPPA in THF (0.6 eq) were added at RT. The formation of a precipitate was observed. Stirring was continued for 1 h at RT after which time HPLC-MS indicated complete conversion. The mixture was used without further treatment in the next reaction (quant). (ES+) m/z 538 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)[OH:30].C(N(CC)CC)C.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[Cl:37][C:33]1[CH:32]=[C:31]([C@@H:29]([OH:30])[CH2:28][NH:27][CH:22]2[CH2:21][CH2:20][N:19]([C:16]3[CH:17]=[CH:18][C:13]([NH:12][S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:11])=[O:10])=[CH:14][CH:15]=3)[CH2:24][CH2:23]2)[CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4cccc(Cl)c4)CC3)cc2)cc1

Procedure:
A mixture of 4-methoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 218) (0.288 g, 0.8 mmol) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloride (which was obtained in Example 1) (0.832 g, 4.0 mmol) was dissolved in 50 mL of methanol and the pH was adjusted to 5 with triethylamine. After stirred at room temperature for one day acetic acid (1 mL) and NaCNBH3 (50 mg, 0.8 mmol) were then added. The reaction was stirred for another day, the solvent was removed, and the residue was purified by thin layer chromatography (10% methanol/CH2Cl2) to give the title compound as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.60 (m, 2 H), 1.95–2.10 (m, 2 H), 2.50–3.10 (m, 5 H), 3.50–3.70 (m, 2 H), 3.79 (s, 3 H), 4.80–4.90 (m, 1 H), 6.79 (d, J=9.0 Hz, 2 ) 6.89 (d, J=9.0 Hz, 2 H), 7.05 (d, J=9.0 Hz, 2 H), 7.30–7.50 (m, 4 H), 7.60 (d, J=9.0 Hz, 2 H), 9.60 (brs, 1 H); MS (ES) m/z: 516.2 (MH+); HRMS Calcd. for C26H31ClN3O4S (MH+); 516.1724. Found: 516.1713.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][O:7]1)C.O.[NH2:13][NH2:14]>C(O)CCC>[O:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[CH2:5][C:4]([NH:13][NH2:14])=[O:3]
Reactant: CCOC(=O)CC1CCCO1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: NNC(=O)CC1CCCO1

Procedure:
A solution of (rac.)-(tetrahydro-furan-2-yl)-acetic acid ethyl ester (3.84 g, 24 mmol) in n-butanol (24 mL) was treated with hydrazine hydrate (1.4 mL, 29 mmol) and the resulting mixture was then heated under reflux for 3 h. The solvent was evaporated and residual volatile components were azeotropically removed by coevaporation with toluene. Chromatographic purification (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a viscous, colorless oil (1.1 g, 32%). 1H-NMR (300 MHz, DMSO): δ=1.45 (mc, 1H), 1.70-1.95 (m, 3H), 2.13 (dd, J=6 Hz, J=14 Hz, 1H), 2.24 (dd, J=7 Hz, J=14 Hz, 1H), 3.56 (dd, J=8 Hz, J=14 Hz, 1H), 3.72 (dd, J=7 Hz, J=14 Hz, 1H), 4.05 (mc, 1H), 4.16 (s, 2H), 8.94 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)=[N:20][CH:21]=3)=[O:15])[C@H:11]([C:27]([F:30])([F:29])[F:28])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:32]12[CH2:38][C@H:35]([NH:36][CH2:37]1)[CH2:34][O:33]2>>[CH:24]1([CH2:23][O:22][C:19]2[N:18]=[CH:17][C:16]([C:14](=[O:15])[CH2:13][N:12]3[C:4]4=[N:3][C:2]([N:36]5[CH2:37][C@@H:32]6[CH2:38][C@H:35]5[CH2:34][O:33]6)=[CH:7][C:6](=[O:8])[N:5]4[CH2:9][CH2:10][C@H:11]3[C:27]([F:29])([F:28])[F:30])=[CH:21][N:20]=2)[CH2:25][CH2:26]1
Reactant: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1cnc(OCC2CC2)nc1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Product: O=C(CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F)c1cnc(OCC2CC2)nc1

Procedure:
160 mg (0.36 mmol) of (8S)-2-chloro-9-[2-(2-cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 58.66 mg (0.43 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride were used in the reaction. After purification by chromatography on silica gel (eluent: 60/40 DCM/MeOH), 125 mg of (8S)-9-[2-(2-cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.Cl.[CH2:15]([NH:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>C(O)C>[CH2:15]([N:22]1[C:5](=[O:7])[CH2:4][CH2:3][C:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NNCc1ccccc1
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1CCC(c2ccccc2)=NN1Cc1ccccc1
Yield: 12.1 %

Procedure:
To a solution of 4-oxo-4-phenylbutanoic acid (1.0 g) in ethanol (28 mL) were added benzylhydrazine hydrochloride (1.1 g) and sodium acetate (4.2 g) at room temperature, and the mixture was heated under reflux overnight. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.18 g).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH:24]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH:40]([CH2:41][CH2:42][CH2:43][C:44]3[S:48][C:47]([C:49]([O:51][CH:52]([CH3:54])[CH3:53])=[O:50])=[CH:46][CH:45]=3)[C:39](=[O:55])[NH:38][C:37]2=[O:56])=[CH:32][CH:31]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[C:24]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH:40]([CH2:41][CH2:42][CH2:43][C:44]3[S:48][C:47]([C:49]([O:51][CH:52]([CH3:53])[CH3:54])=[O:50])=[CH:46][CH:45]=3)[C:39](=[O:55])[NH:38][C:37]2=[O:56])=[CH:32][CH:31]=1)(=[O:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC(O)c1ccc(N2C(=O)NC(=O)C2CCCc2ccc(C(=O)OC(C)C)s2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCCCC(=O)c1ccc(N2C(=O)NC(=O)C2CCCc2ccc(C(=O)OC(C)C)s2)cc1
Yield: 58 %

Procedure:
Dess-Martin periodinane (9 mg, 0.021 mmol) was added to a solution of 31 (9 mg, 0.016 mmol) in CH2Cl2 (0.16 mL) at room temperature. After 4 h the reaction mixture was diluted with 20% EtOAc/hexanes (2 mL) and filtered through celite, washing with additional 20% EtOAc/hexanes (2 mL). The filtrate was concentrated in vacuo. The crude residue was purified on 4 g silica (hexanes→EtOAc, gradient) to afford 4.5 mg (56%) of the title compound (32).
Reaction SMILES: C([N:8]1[CH2:25][CH:24]([CH2:26][OH:27])[O:23][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[OH:27][CH2:26][CH:24]1[O:23][C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[CH2:9][NH:8][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)CC(CO)O2
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(CO)O2
Temperature: 50 °C
Yield: 89.8 %

Procedure:
To a solution of tert-butyl 8-benzyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (2.00 g, 5.31 mmol) in methanol (38 mL) was added Pd(OH)2 (671 mg, 4.78 mmol) and ammonium formate (4.02 g, 63.7 mmol) and the mixture heated at 50° C. for 1 h. Additional catalyst (2.6 mmol) and ammonium formate (25 mmol) were added and the reaction heated for an additional 2 h. The reaction mixture was filtered and concentrated to ˜10 mL volume. The concentrate was diluted with dichloromethane and saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer washed with dichloromethane (5×50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to provide tert-butyl 10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.37 g, 4.77 mmol, 90%) as an amber-colored glass. ESI-MS m/z calc. 286.2. Found 287.3 (M+1)+; Retention time: 0.65 minutes (3 min run).
Reaction SMILES: [Br:1][CH:2](Br)[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[CH:6]=1)=[O:4].C(N(CC)CC)C.P([O-])(OCC)OCC>O1CCCC1>[Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: O=C(c1ccc2cc(Br)ccc2c1)C(Br)Br
Agent: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc2cc(Br)ccc2c1
Reaction time: 8 h
Yield: 97 %

Procedure:
2,2-dibromo-1-(6-bromonaphthalen-2-yl)ethanone (90.0 g, 221 mmol, 1.00) was dissolved in tetrahydrofurane (800 mL), triethylamine (27.67 mL, 199 mmol, 0.9 equiv.) was added followed by diethyl phosphite (45.8 g, 332 mmol, 1.50 equiv.). The reaction mixture was stirred overnight. The reaction mixture was filtrated and the solvent was removed in vacuum. The obtained residue was dissolved in ethyl acetate (1.2 L) and washed with water. The organic layer was separated, dried over sodium sulphate, filtrated and concentrated to yield crude 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (70.3 g). Recrystallization from acetonitrile gave 30 g (first batch) and 6.5 g (second batch) of 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (50%)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]([OH:12])=O)[N:7]=[N:6]1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:12])[N:7]=[N:6]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1cn(Cc2ccccc2Cl)nn1
Solvent: CCO
Product: O=C(c1cn(Cc2ccccc2Cl)nn1)N1CCCCC1

Procedure:
In a manner analogous to that described in Example 14, starting from 11.8 g (50 mmol) of 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid, converting this into the acid chloride and treating the latter with piperidine (50 mmol), there is obtained 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid piperidide having a melting point of 141°-142° (from ethanol) and, by treating the acid chloride with dimethylamine (50 mmol), there is obtained 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid N,N-dimethylamide having a melting point of 120°-121° (from ethanol).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:33].CCO.[OH-].[NH4+:38]>O>[NH2:38][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:33]
Reactant: [NH4+]
Reactant: O=S(=O)(c1cnc(Cl)c(F)c1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ncc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 125 °C
Yield: 53.7 %

Procedure:
A 100-mL pressure vessel was charged with 2-(4-(4-((6-chloro-5-fluoro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.725 g, 1.389 mmol), 5 mL of EtOH, and concentrated ammonium hydroxide (10 mL, 257 mmol). The vessel was sealed and the mixture was heated to 125° C. for 18 h. After that time, the mixture was diluted with water and extracted with CH2Cl2 (3×100 mL). The combined extracts were dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (0 to 70% EtOAc in hexanes) and to give 2-(4-(4-((6-amino-5-fluoro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.375 g) as a white solid. 1H NMR (400 MHz, CD3OD) δ=8.18 (d, J=1.4 Hz, 1H), 7.62 (dd, J=1.9, 10.5 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.01 (d, J=9.0 Hz, 2H), 3.35-3.29 (m, 4H), 3.19-3.14 (m, 4H). m/z (ESI, +ve ion) 503.1 (M+H)+. GK-GKRP IC50 (Binding)=0.163 μM; GK-GKRP EC50 (LC MS/MS-2)=0.299 μM.