Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:24])[CH2:10][C@@H:11]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][C:13]([NH2:15])=[O:14])C1C=CC=CC=1>C(OCC)(=O)C.[Pd].ClCCl.CCCCC>[Si:17]([O:16][C@H:11]([CH2:10][C:9]([OH:24])=[O:8])[CH2:12][C:13]([NH2:15])=[O:14])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCC
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)O
Temperature: 5 °C

Procedure:
(S)-Benzyl-3-(tert-butyl dimethylsilyloxy)glutaramate (100 g) was dissolved in ethyl acetate and placed in pressure flask. To this Palladium on charcoal (5%, 1 g) was added and stirred under hydrogen atmosphere (˜2.8 Kg). Palladium was removed by filtration. The filtrate was mixed with water and adjusted pH to ˜9.0 by using Aq ammonia solution. The reaction mass was stirred and layers were separated. The aqueous phase was washed with dichloromethane and dichloromethane was added to aqueous phase. The reaction mass was cooled to 5° C. and pH was adjusted to 4.0 with Aq phosphoric acid. The reaction mass was stirred and layers were separated. The organic phase was washed with water and dried over sodium sulphate. The organic layer was evaporated under vacuum to yield residue. Residue was dissolved in dichloromethane and to this solution pentane was added, stirred, filtered and dried to yield (S)-3-(tert-butyl dimethylsilyloxy)glutaric acid monoamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[OH-].[K+].Cl[C:13]([F:23])([F:22])C(C1C=CC=CC=1)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]([F:23])[F:22])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: FC(F)Oc1ccc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 40 h
Yield: 52 %

Procedure:
A solution of 4-bromo-2-chlorophenol (830 mg) and a 30% potassium hydroxide solution (16 mL) in acetonitrile (16 mL) was cooled to −78° C. 2-Chloro-2,2-difluoroacetophenone (2.95 mL) was added and the mixture was stirred at 80° C. for 40 hours. The reaction solution was cooled to room temperature and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→10:1) to give 4-bromo-2-chloro-1-(difluoromethoxy)benzene as a colorless oil (533 mg, 52%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][C:16]=1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC>CS(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:5][C:6](=[O:7])[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:16]([CH3:22])[CH:17]=1
Reactant: Cc1cc(I)ccc1OCC1CCCN1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)OC(C)(C)C)c(C)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 111.7 %

Procedure:
To a stirred solution of 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-1iodo-3-methylbenzene (645.3 mg, 1.546 mmol) in DMSO (7 mL) and MEOH (6 mL) was added Et3N (0.47 mL, 3.401 mmol), Pd(OAc)2 (17.4 mg, 0.077 mmol) and 1,3-bis(diphenylphosphino) propane (31.46 mg, 0.077 mmol). To the stirred mixture was induced CO gas for 10 min. The mixture was stirred at 70° C. for 2 days and concentrated. The residue was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure, and the residue was chromatographed on silica-gel with n-hexane-EtOAc (5:1, v/v) as eluent to afford 301.6 mg (56%) methyl4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-methylbenzoate as an oil. 1H-NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 1.86–2.10 (br m, 4H), 2.33 (s, 3H), 3.32–3.50 (br m, 2H), 3.88 (s, 3H), 3.88, 4.04 (br m each, 1H), 4.13–4.20 (m, 2H), 6.89 (br m, 1H), 7.82 (s, 1H), 7.85 (dd, J=2.0, 8.8 Hz, 1H); MS (FAB) m/z 350 (M++1).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH3:13])=[N:7][NH:8]2.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH3:13][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:8][N:7]=1
Reactant: BrCc1ccccc1
Reactant: Cc1n[nH]c2cccc(O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1n[nH]c2cccc(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (0.452 g of a 60% dispersion in mineral oil, 11.3 mmol) in DMF (30 mL) was added 4-hydroxy-3-methylindazole (1.52 g, 10.3 mmol) (prepared in a similar manner to that described in J. Med Chem., 2000, 2672) in DMF (20 mL) via a cannula. The mixture was stirred at room temperature for 10 minutes and then benzyl bromide (1.223 mL, 10.3 mmol) was added and stirring was continued at room temperature for 2 hrs. The mixture was quenched with ammonium chloride solution and the DMF was evaporated. Ethyl acetate and water were added and the product was extracted into ethyl acetate and the extracts were dried (Na2SO4) and evaporated. Chromatography (0-100% ethyl acetate in hexane) gave the title compound (D30) as an orange solid (1.774 g, containing ˜10% dibenzylated material).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][CH2:25][OH:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH:27]([C:29]1([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:31][CH2:30]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:27][C:29]2([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][CH2:31]2)[CH2:24][CH2:25][OH:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CNCCO)ccc1Cl
Reactant: CC(C)(C)OC(=O)NC1(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(CN(CCO)Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Yield: 83.4 %

Procedure:
2-Chloro-5-[[(2-hydroxyethyl)amino]methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.250 g, Example 71c), (1-formylcyclopropyl)-carbamic acid, 1,1-dimethylethyl ester (0.260 g), sodium triacetoxyborohydride (0.600 g) and dichloromethane (50 ml) were stirred together under nitrogen for 24 h. The mixture was poured into saturated aqueous sodium hydrogencarbonate solution, extracted into dichloromethane, dried over magnesium sulfate, filtered and concentrated under reduced to pressure. The crude material was purified on silica gel (ethyl acetate), to afford the subtitled compound (0.302 g).
Reaction SMILES: CCN(C(C)C)C(C)C.Br[C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)=[CH:18][C:17]=2[O:28][CH3:29])=[N:14][N:15]=1.[CH2:30]1[C:33]2([CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]2)[CH2:32][NH:31]1.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.C(Cl)Cl.CO>[CH3:29][O:28][C:17]1[CH:18]=[C:19]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[CH:20]=[CH:21][C:16]=1[C:13]1[S:12][C:11]([N:31]2[CH2:32][C:33]3([CH2:38][CH2:37][CH2:36][NH:35][CH2:34]3)[CH2:30]2)=[N:15][N:14]=1
Reactant: COc1cc(-c2cnn(C)c2)ccc1-c1nnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CNC2)C1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cnn(C)c2)ccc1-c1nnc(N2CC3(CCCNC3)C2)s1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
DIPEA (116 μL, 0.666 mmol) was added to a stirred suspension of 2-bromo-5-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole (78 mg, 0.222 mmol) and tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate (acetic acid salt, 127 mg, 0.444 mmol) in NMP (444 μL) and the mixture was heated at 120° C. for 3 hours. The reaction mixture was diluted with DCM (10 mL), washed with saturated NaHCO3(aq) (10 mL), and the organic phase was separated. TFA (342 μL, 4.44 mmol) was added and the resulting solution was stirred at room temperature for 18 hours. A further 1 mL TFA was added and the reaction mixture was warmed to 35° C. and stirred for 48 hours. The reaction mixture was loaded onto a 1 g SCX cartridge (pre-wet with MeOH) and the cartridge was washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the crude product as a brown oil. The crude material was purified by UV directed preparative HPLC under acidic conditions (TFA modified) and the product containing fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10 mL) and flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound a white foam-like solid (40.5 mg, 46% yield). LC-MS: Rt 0.83 min; MS m/z 397.1 [M+H]+ [Method D], 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 8.06 (d, J=8.08 Hz, 1H), 7.99 (s, 1H), 7.37 (d, J=1.52 Hz, 1H), 7.29 (dd, J=8.08, 1.52 Hz, 1H), 4.00 (s, 3H), 3.88 (s, 3H), 3.81 (d, J=7.58 Hz, 2H), 3.74 (d, J=7.58 Hz, 2H), 2.82 (s, 2H), 2.60 (t, J=5.05 Hz, 2H), 1.73 (t, J=5.56 Hz, 2H), 1.41 (quin, J=5.56 Hz, 2H).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:26])[CH3:25])[CH:16]=[N:17][C:10]=2[N:9]([CH3:32])[C:8]1=[O:33])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:26])[CH3:25])[CH:16]=[N:17][C:10]=2[N:9]([CH3:32])[C:8]1=[O:33]
Reactant: CC(C)CCc1c(-c2ccccc2C(C)C)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CCc1c(-c2ccccc2C(C)C)cnc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.2 %

Procedure:
To a solution of 3-(5-isopentyl-6-(2-isopropylphenyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (15 mg, 0.033 mmol) in THF (4 mL) and water (4 mL) was added LiOH.H2O (2.79 mg, 0.066 mmol). The reaction was stirred at RT for 15 min then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1) to give 3-(3-hydroxypropyl)-5-isopentyl-6-(2-isopropylphenyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (8 mg, 56.8% yield) as a white solid. 1H NMR (CDCl3) δ: 8.35 (s, 1H), 7.43-7.42 (d, J=4.0 Hz, 2H), 7.28-7.24 (m, 1H), 7.07-7.05 (m, 1H), 4.27 (m, 3H), 3.76 (s, 3H), 3.58 (s, 2H), 3.40-3.31 (m, 2H), 2.68-2.54 (m, 2H), 1.97-1.94 (m, 2H), 1.57 (m, 1H), 1.22-1.19 (m, 3H), 1.08-1.06 (m, 3H), 0.71-0.69 (m, 3H), 0.64-0.62 (d, J=8 Hz, 3H). LCMS: MH+ 424 and TR=3.546 min.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:24]4[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[CH:25]=4)[CH:5]=3)=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2cccc(F)c2)cn1
Yield: 12 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 3-fluorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (13 mg, 12%) which was obtained as an off-white solid. MS: m/e=338.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.CC(C)C(O)=O.[CH3:13][N:14]([CH3:17])[CH:15]=O>>[CH3:13][N:14]([CH3:17])[CH:15]=[N:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: CN(C)C=O
Reactant: Nc1nccs1
Solvent: CC(C)C(=O)O
Product: CN(C)C=Nc1nccs1

Procedure:
prepared by reaction of 2-aminothiazole with N,N-dimethylformamide dimethyl acetate. LC-MS: tR=0.40 min; [M+H]+=156.0.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:15]1[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:16]=1.C(N(CC)CC)C>>[CH2:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:15]2[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[N:16]=2)[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC2CCNC2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CCN(CC)CC
Product: Cn1c(N2CCC(OCc3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 70 %

Procedure:
A solution of 3-benzyloxypyrrolidine (182 mg, 1.03 mmol), 2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (181 mg, 0.82 mmol) and triethylamine (387 mmol, 3.83 mmol) was refluxed for 3 hours. After removal of the solvent, the residue was purified by silica gel column chromatography (eluent; dichloromethane/ethanol=10/1) and washed with ethyl acetate to afford 2-(3-benzyloxy-pyrrolidin-1-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (208 mg, 70%).
Reaction SMILES: [OH:1][NH:2][CH2:3][C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][NH:23][OH:24])=[CH:18][CH:17]=3)[CH:10]=2)=[CH:6][CH:5]=1.Cl[C:28]([N:30]=[C:31]=[O:32])=[O:29]>O1CCCC1>[O:29]=[C:28]1[NH:30][C:31](=[O:32])[O:24][N:23]1[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:7]3[CH:25]=[CH:26][C:4]([CH2:3][N:2]4[C:31](=[O:32])[NH:30][C:28](=[O:29])[O:1]4)=[CH:5][CH:6]=3)[CH:10]=2)=[CH:17][CH:18]=1
Reactant: O=C=NC(=O)Cl
Reactant: ONCc1ccc(Oc2cccc(Oc3ccc(CNO)cc3)c2)cc1
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n(Cc2ccc(Oc3cccc(Oc4ccc(Cn5oc(=O)[nH]c5=O)cc4)c3)cc2)o1
Reaction time: 0.17 h

Procedure:
1,3-Bis[4-(N-hydroxyaminomethyl)phenoxy]benzene (0.704 g) was dissolved in 21 ml of tetrahydrofuran to which, with ice-cooling and in an atmosphere of argon, was subsequently added dropwise 0.354 ml of chlorocarbonyl isocyanate. After 10 minutes of stirring at the same temperature, the stirring was continued for 2 hours at room temperature. The solvent was evaporated under a reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 0.44 g of 1,3-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene from fractions of chloroform-methanol (30:1) elution.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([CH2:35][OH:36])([OH:34])[CH2:30][CH2:29]2)[C:9]=1[Br:37].Cl>O1CCOCC1>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([CH2:35][OH:36])([OH:34])[CH2:30][CH2:29]2)[C:9]=1[Br:37]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(C2CCC(O)(CO)CC2)nc2c(-c3cnn(-c4ccccc4)c3)cnn12
Agent: Cl
Solvent: C1COCCO1
Product: Nc1c(Br)c(C2CCC(O)(CO)CC2)nc2c(-c3cnn(-c4ccccc4)c3)cnn12
Temperature: 40 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanol (542 mg, 0.729 mmol) in dioxane (4 mL) was added HCl (4 N, aq, 4 mL) at rt. The resulting mixture was stirred at 40° C. for 1 h. The reaction mixture was evaporated to dryness to afford 4-(7-amino-6-bromo-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanol as a gray solid (296 mg), which was used without further purification. HPLC-MS TR=1.08 min (UV 254 nm, 3 min method); mass calculated for formula C22H23BrN6O2 482.1, observed LCMS m/z 483.1 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:7]([CH2:26][CH2:27][CH3:28])[N:6]2[N:29]=[C:30]([CH3:32])[N:31]=[C:5]12.[H-].[Na+].[CH3:39]N(C)C=O.CI>C(OCC)(=O)C>[CH3:39][O:1][CH:2]([C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)=[C:7]([CH2:26][CH2:27][CH3:28])[N:6]2[N:29]=[C:30]([CH3:32])[N:31]=[C:5]12
Reactant: CN(C)C=O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)C(C)(C)C)c2nc(C)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(OC)C(C)(C)C)c2nc(C)nn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A mixture of 4′-{[4-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.3 g), sodium hydride (0.03 g) and N,N-dimethylformamide (5 mL) was stirred at 0° C. for 10 min, methyl iodide (0.046 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.22 g, 72%).
Reaction SMILES: [F:1][C:2]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]([OH:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].C(OC(=O)C)(=O)C.[C:23]1(=[N:27]O)[CH2:26][CH2:25][CH2:24]1>N1C=CC=CC=1.CC(C)=O>[F:1][C:2]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]([O:8][N:27]=[C:23]2[CH2:26][CH2:25][CH2:24]2)[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10]
Reactant: ON=C1CCC1
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1O
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1ON=C1CCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate (6.60 g., 30 mmoles), acetic anhydride (3.27 g., 32 mmoles), pyridine (10 ml.) and acetone (10 ml.) were mixed and allowed to stand overnight at ordinary temperature (18°-23° C.). To this mixture were added cyclobutanone oxime (3.82 g., 45 mmoles) and pyridine (5 ml.) which was heated at 60° C. for 2 hours. Then, volatiles were removed under reduced pressure and the remaining mass was chromatographed on a column of silica gel with chloroform/acetone=85/15(V/V) to give 4.78 g of ethyl 5-fluoro-6-cyclobutylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate.
Reaction SMILES: [H-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[O:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:10][CH2:9]1>O1CCCC1>[N+:3]([CH2:6][C:8]1([OH:7])[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:12][CH2:13]1)([O-:5])=[O:4]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: C[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(C[N+](=O)[O-])CC3)c(F)c2)C(=O)O1
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a stirred suspension of sodium hydride (0.72 g, 17.0 mmol) in dry tetrahydrofuran (40 ml) was added nitromethane (12.4 mmol) at 0° C. temperature. It was further stirred for 30 minutes and then (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (7.2 mmol) was added. The reaction mixture was stirred at 65° C. for 24 hours. The reaction mixture was poured on to crushed ice. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The removal of solvent afforded a crude compound, which was purified by column chromatography over silica gel to afford title compound in 17% yield. M.P. 186-187° C. and MS (M+1)=384 (MH+, 100%) M.F.=C18H23FN4O6.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:5][C@H:4]([CH2:6][OH:7])[CH2:3]1.[C:8](=O)([O:17]N1C(=O)CCC1=O)[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(#N)C.CC(O)C>C(N(CC)CC)C>[OH:7][CH2:6][C@@H:4]1[CH2:5][C@H:2]([NH:1][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1
Reactant: N[C@H]1C[C@@H](CO)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1C[C@@H](CO)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6.0 g of {cis-3-[(benzyloxy)methyl]cyclobutyl}amine, 2 g of 20% palladium hydroxide on carbon, 200 mL of methanol and 20 mL of acetic acid was stirred at room temperature under an atmosphere of hydrogen (balloon) for 24 h. The mixture was filtered to remove catalyst and concentrated under reduced pressure. Further drying under vacuum gave 6.5 g of the acetate salt of (cis-3-aminocyclobutyl)methanol as a thick resin. A mixture of 6.5 g of the acetate salt of (cis-3-aminocyclobutyl)methanol, 8 g of benzyl succinimidyl carbonate, 150 mL of anhydrous acetonitrile 15 mL of 2-propanol and 20 mL of triethylamine was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and partitioned between 2×150 mL of ethyl acetate and 50 mL of water. The combined extracts were dried over magnesium sulfate and concentrated to dryness. Chromatography using a gradient of 25% to 75% ethyl acetate in hexane gave 10.8 g of product as a crystalline solid: MS (m+1)=236.3; 1H NMR (400 MHz, CDCl3) 7.37 (m, 5H), 5.18 (s, 2H), 4.92 (br s, 1H), 4.1 (m, 1H), 3.58 (s, 2H), 2.42 (dd, 2H), 2.1 (m, 1H), 1.7 (dd, 2H).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:10][C:11]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH:20]([CH3:22])[CH3:21])[O:13][N:12]=1>C1COCC1>[CH:1]1([O:6][CH2:10][C:11]2[C:15]([C:16]([O:18][CH:19]3[CH2:3][CH2:2][CH2:1][CH2:5]3)=[O:17])=[C:14]([CH:20]([CH3:22])[CH3:21])[O:13][N:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c(CBr)noc1C(C)C
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1onc(COC2CCCC2)c1C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
A solution of cyclopentanol (0.44 mL, 4.8 mmol), in THF (10 mL), was stirred at 0° C. as sodium hydride 60% oil dispersion (192 mg, 4.8 mmol) was added. The solution was allowed to stir for 30 minutes. A solution of methyl 3-(bromomethyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (500 mg, 1.91 mmol), in THF (5 mL) was then added and the resulting solution was allowed to warm to room temperature and stir for 3 hours. The solution was then partitioned between brine and ethyl acetate. The organic layer was dried with MgSO4, filtered and concentrated. The residue purified by chromatography (silica gel, hexane to 1:4 ethyl acetate:hexanes). Fractions containing the product were combined and concentrated to yield cyclopentyl 3-[(cyclopentyloxy)methyl]-5-(1-methylethyl)-4-isoxazolecarboxylate (94 mg, 15%). 1H NMR (400 MHz, DMSO-d6): δ 5.29-5.26 (m, 1H), 4.54 (s, 2H), 3.98 (m, 1H), 3.64 (septet, 7 Hz, 1H), 1.85 (m, 2H), 1.72-1.56 (m, 12H), 1.47-1.40 (m, 2H), 1.25 (d, J=7 Hz, 6H). ESI-LCMS m/z 322 (M+H)+.