Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([C:15](OCC)=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1([CH2:15][OH:16])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 105.8 %

Procedure:
To a 0° C. solution of 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (3.0 g, 10.90 mmol) in 55 mL THF was added 1M lithium aluminum hydride in THF (21.79 mL, 21.79 mmol). The reaction mixture was stirred at 0° C. for 3.5 hours, after which it was carefully quenched by the addition of 1:1 Na2SO4-10H2O:Celite, diluted with THF, warmed to ambient temperature, and stirred vigorously for 2 hours. The slurry was vacuum filtered through GF/F paper on a Buchner funnel, rinsed with THF, and the filtrate was concentrated in vacuo to give the title compound (2.69 g) as a clear colorless oil, which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>[Pt].ClCCl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:9])=[CH:25][CH:26]=1
Reactant: CCCCCCCCCCCCCCOC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOC(=O)c1ccc(N)cc1
Yield: 65.2 %

Procedure:
Under a nitrogen purge, 10% platinum on carbon (2.5 grams) was added to a mixture of tetradecyl 4-nitrobenzoate (25 grams, 69 mmol) and ethyl acetate (250 milliliters) in a Parr vessel. The vessel was placed under hydrogen pressure (49 psi, 3.3×105 Pa) for sixteen hours. Dichloromethane was added and the reaction mixture was filtered through a layer of CELITE filter aid. The filtrate was concentrated under reduced pressure to a tan solid. The solid was recrystallized from ethanol to obtain 15 grams of tetradecyl 4-aminobenzoate as light tan needles.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][CH2:7][C:8](=[O:9])[C:2]1=2.Cl.[NH2:11]O.CC([O-])=O.[Na+]>CO>[S:1]1[C:2]2[C:8](=[O:9])[NH:11][CH2:7][CH2:6][C:3]=2[CH:4]=[CH:5]1
Reactant: O=C1CCc2ccsc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1NCCc2ccsc21
Temperature: 130 °C
Yield: 56.3 %

Procedure:
A solution of 4H-cyclopenta[b]thiophen-6(5H)-one (1.34 g, 9.7 mmol), hydroxylamine HCl (1.45 g, 20.8 mmol) and NaOAc (7.3 g, 89.0 mmol) in MeOH (150 mL) was stirred overnight at room temperature. The reaction was then concentrated under reduced pressure, taken up in EtOAc (100 mL) and filtered over a plug of silica gel, eluting with EtOAc. The filtrate was concentrated, taken up in polyphosphoric acid (100 g) and heated for 2 h at 130° C. Upon completion, the reaction was quenched by pouring over ice water (100 mL). The aqueous mixture was extracted with DCM (2×100 mL) and the combined extracts were washed with 0.1 M NaOH (100 mL), dried over Na2SO4, then filtered and concentrated. 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (837 mg, 55% yield) was isolated as a white solid after purification by flash chromatography over silica gel (20-30% EtOAc/hexane eluent). 1H NMR (300 MHz, MeOH) δ ppm 7.69 (d, J=5.0 Hz, 1H), 7.06 (d, J=5.0 Hz, 1H), 3.57 (t, J=7.1 Hz, 2 H), 2.94 (t, J=7.1 Hz, 2H); MS (EI) m/z=154.2 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=1>ClCCl>[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:21])=[C:18]([C:25]([F:26])([F:27])[F:28])[CH:17]=1
Reactant: Cc1ccc(C(=O)Cl)c(C(F)(F)F)c1
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCNC(=O)C2)c(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.400 g, 4 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (20 mL), and to this was added triethylamine (0.669 mL, 4.80 mmol). The solution was then cooled to 0° C. before 4-methyl-2-(trifluoromethyl)benzoyl chloride (I62) (0.979 g, 4.40 mmol) in dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then re-dissolved in DCM (40 mL) and washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL) and brine (20 mL), before being dried over anhydrous sodium sulphate. The sodium sulphate was then removed by filtration and the solvent was evaporated in vacuo. The remaining solid was then stirred in hexane (40 mL) at 55° C. for 30 minutes. The solid was then removed by filtration to yield the product in 1.110 g.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[OH:23].[Cl:24][C:25]1[CH:26]=[C:27]([CH:33]=O)[CH:28]=[N:29][C:30]=1[CH2:31][OH:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[Cl:24][C:25]1[CH:26]=[C:27]([CH2:33][NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:22])[CH2:4][C@H:3]2[OH:23])[CH:28]=[N:29][C:30]=1[CH2:31][OH:32]
Reactant: O=Cc1cnc(CO)c(Cl)c1
Reactant: COc1cnc2ccc(=O)n(CCN3CC[C@H](N)[C@H](O)C3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: COc1cnc2ccc(=O)n(CCN3CC[C@H](NCc4cnc(CO)c(Cl)c4)[C@H](O)C3)c2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-{2-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one (Intermediate 33 as a free base: 200 mg, 0.628 mmol) and 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (108 mg, 0.628 mmol) in DCE (10 ml) and Methanol (0.5 ml) was stirred at room temperature overnight. Sodium triacetoxyborohydride (399 mg, 1.885 mmol) was added. The mixture was stirred under N2 at rt for 6 h. LCMS showed imine and desired compound. An excess of sodium triacetoxyborohydride (399 mg, 1.885 mmol) was added. The mixture was stirred overnight. Full conversion to the amine was observed by LCMS. It was quenched with saturated NaHCO3, extracted with DCM/MeOH 9/1, dried (MgSO4), filtered, and concentrated affording 242 mg of crude material. Purification by manual flash chromatography using a 5 g Merck silica gel cartridge, and DCM/MeOH 9/1 as eluent afforded 1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one (179.8 mg, 0.360 mmol, 57% yield) as a white solid.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:12]([OH:14])=[O:13].[C:15]([O-])([O-])=O.[K+].[K+].CI.Cl>CN(C=O)C>[CH2:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: C=C1CCCC2(CCCC2)C1C(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=C1CCCC2(CCCC2)C1C(=O)OC
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
At 5° C., a solution of the previously obtained 7-methylenespiro[4.5]decane-6-carboxylic acid (1.1 g, 5.66 mmol, prepared as described in Example 28) in DMF (20 ml) was treated with K2CO3 (0.86 g, 6.8 mmol). The resulting mixture was stirred for 30 min., treated with methyl iodide (0.53 ml, 8.5 mmol), stirred at 20° C. for 2 h, poured into cold 2N aqueous HCl (30 ml), and extracted twice with hexane (50 ml). The combined organic phases were washed with water (50 ml), with a saturated aqueous solution of NaCl (50 ml), dried (MgSO4), and concentrated. FC (30 g SiO2, hexane/MTBE 50:1) of the crude product (1 g) gave methyl 7-methylenespiro[4.5]decane-6-carboxylate (0.84 g, 71%). Boiling point: 90° C. (1.1 mbar).
Reaction SMILES: [CH2:1]([C:3]([OH:10])([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].[CH:11]12[CH2:17][CH:14]([CH:15]=[CH:16]1)[CH2:13][CH:12]2[CH2:18][CH2:19][C:20](OC)=[O:21]>>[CH:11]12[CH2:17][CH:14]([CH:15]=[CH:16]1)[CH2:13][CH:12]2[CH2:18][CH2:19][C:20]([O:7][CH2:6][CH2:5][CH2:4][C:3]([CH2:8][CH3:9])([OH:10])[CH2:1][CH3:2])=[O:21]
Reactant: CCC(O)(CC)CCCO
Reactant: COC(=O)CCC1CC2C=CC1C2
Product: CCC(O)(CC)CCCOC(=O)CCC1CC2C=CC1C2
Yield: 91 %

Procedure:
By following the procedure of Synthesis Example 2 except that 4-ethyl-1,4-hexanediol was used instead of 4-methyl-1,4-pentanediol and methyl 3-(5-norbornen-2-yl)propionate used instead of methyl 5-norbornene-2-carboxylate, there was obtained 4-ethyl-4-hydroxyhexyl 3-(5-norbornen-2-yl)propionate. Yield 91%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][OH:11].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[CH3:22][N:18]1[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=[C:13]([O:11][CH2:10][C:3]3[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:23]=[C:17]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(F)cc1F
Product: CN1CCCn2c1cc(OCc1cc(F)c(F)cc1F)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (2,4,5-trifluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [C:1]([N:5]1[C:12]2[C@@H:11]3[CH2:13][C@@H:10]3[CH2:9][C:8]=2[C:7]([C:14](O)=[O:15])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[C:48]1([C:54]([NH2:57])([CH3:56])[CH3:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[CH3:55][C:54]([NH:57][C:14]([C:7]1[C:8]2[CH2:9][C@H:10]3[CH2:13][C@H:11]3[C:12]=2[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:6]=1)=[O:15])([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH3:56]
Reactant: CC(C)(C)n1nc(C(=O)O)c2c1[C@@H]1C[C@@H]1C2
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1nn(C(C)(C)C)c2c1C[C@H]1C[C@@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
To a solution of (1aR,5aR)-2-tert-butyl-1a,2,5,5a-tetrahydro-1H-2,3-diazacyclopropa[a]pentalene-4-carboxylic acid (30 mg, 0.136 mmol), HATU (55 mg, 0.143 mmol) in DMF (1 mL) was added Et3N (16 mg, 0.15 mmol). After stirring for 5 min at room temperature, 2-phenylpropan-2-amine (20 mg, 0.143 mmol) was added into the reaction. The reaction was stirred for 1 h at room temperature, and purified by preparative HPLC to give the title compound (25 mg). LCMS m/z=338.5 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.34 (td, J=4.5 and 3.4 Hz, 1H), 1.11 (td, J=7.8 and 4.5 Hz, 1H), 1.63 (s, 9H), 1.78 (s, 6H), 2.11-2.18 (m, 2H), 2.75 (d, J=16.7 Hz, 1H), 2.86 (dd, J=16.6 and 5.8 Hz, 1H), 7.21 (t, J=7.3 Hz, 1H), 7.32 (t, J=8.0 Hz, 2H), 7.36 (bs, 1H), 7.42-7.46 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>C1(C)C=CC=CC=1.C(O)C.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>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:32]2[CH:31]=[CH:30][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:34][CH:33]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccc(OC(F)(F)F)cc2)C1=O
Temperature: 90 °C
Reaction time: 24 h
Yield: 32.4 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (150 mg) in 15 ml toluene and 5 ml ethanol, were added 30 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of saturated aqueous sodium carbonate, and 100 mg of 4-(trifluoromethoxy)benzeneboronic acid. The reaction solution was stirred at 90° C. for 24 hours. Then the solvent was removed under reduced pressure. The resulting residue was extracted with water and dichloromethane. The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate) to yield 60 mg of 2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-4-{4-(trifluoromethoxy)phenyl}-3(2H)-furanone as a solid. mp: 118-120° C. NMR: δ1.58 (s, 6H), 3.08 (s, 3H), 7.20-7.26 (m, 2H), 7.31-7.34 (m, 2H), 7.82-7.85 (m, 2H), 7.95-7.98 (m, 2H). IR (cm−1): 2931, 1698, 1510, 1387, 1258, 1150, 960, 846, 770.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH:18]([CH3:20])[CH3:19])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>C(O)C>[CH:18]([C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:31][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:21](=[O:23])[CH3:22])=[CH:30][CH:29]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([CH3:20])[CH3:19]
Reactant: CC(C)C1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: CC(=O)Nc1ccc(S)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(SC2=C/C(=C3/C(=O)NN=C3C(C)C)Nc3ccccc32)cc1
Temperature: 180 °C

Procedure:
(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-isopropyl-1H-pyrazol-5(4H)-one (0.029 g, 0.089 mmol) was dissolved in ethanol (1 mL) and 4-acetamidothiophenol (0.016 g, 0.094 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 30 minutes. The mixture was then concentrated and purified by LC-MS to give Example 19. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (d, J=6.82 Hz, 6H) 2.13 (s, 3H) 2.53 (bs, 1H) 6.65 (s, 1H) 7.68-7.70 (m, 3H) 7.86-7.97 (m, 3H) 8.02 (s, 1H) 8.20 (d, J=8.34 Hz, 1H) 10.43 (s, 1H); ESI-MS: m/z calc'd for C23H22N4O2S 418.51. found 419.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C@H:7]([C:16]([OH:18])=[O:17])[O:8][C@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[N+](=[CH2:23])=[N-]>CCOCC>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C@H:7]([C:16]([O:18][CH3:23])=[O:17])[O:8][C@H:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Solvent: CCOCC
Product: COC(=O)[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ether solution of cis-6-chloro-4-phenyl-1,3-benzodioxan-2-carboxylic acid (2.14 g, 7.36 mmoles), chilled in an ice bath, was added an ethereal solution of diazomethane until the yellow color of the diazomethane was no longer discharged. The solution was stirred in the ice bath for 10 minutes at room temp. for 10 minutes, and finally at 35° for 15 minutes. The ether solution was washed with dil.NaHCO3 solution (2 portions), water (2 portions), and saturated brine (1 portion), and dried over anhydrous Na2SO4. The solvent was evaporated to yield a solid which was recrystallized from benzene-Skellysolve B (essentially n-hexane). The yield was 1.71 g (76%); m.p. 129.5°-131°. NMR (CDCl3), β6.6 (d, 1H, C(5)H, cis); 5.65 ppm (s, 1H, C(2)H, cis).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19]([C:23]5[N:28]=[CH:27][C:26](B6OC(C)(C)C(C)(C)O6)=[CH:25][N:24]=5)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.C1C[O:41]CC1>O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:18][N:19]([C:23]5[N:24]=[CH:25][C:26]([OH:41])=[CH:27][N:28]=5)[CH2:20][CH2:21][O:22]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(B6OC(C)(C)C(C)(C)O6)cn5)CCO4)c3n2)cn1
Reactant: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(O)cn5)CCO4)c3n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
(S)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyrimidin-2-yl)morpholine 55 mg (0.11 mmol) was dissolved in THF 2 ml and H2O 2 ml, and NaBO3 16 mg (0.16 mmol) was added, followed by stirring at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (MeOH:MC=1:10), to give (S)-2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-ol 29 mg (two steps: 67%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(O[K])(C)(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][N:30]([C:2]2[C:3]3[CH2:10][CH2:9][N:8]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(CN2CCc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)O[K]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CCc3c(N4CCN(C(=O)OC(C)(C)C)CC4)ncnc32)cc1
Yield: 57.4 %

Procedure:
A solution of 4-Chloro-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (0.36 g, 1.31 mmol), 1-Boc-piperazine (1.0 g, 5.37 mmol) and tBuOK (0.18 g, 1.60 mmol) in NMP (20 mL) was heated to 128° C. for 20 hours. After cooling, the mixture was diluted with ethyl acetate (500 mL) and washed with water (5×150 mL). The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (1:1) to give 4-[7-(4-Methoxy-benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.32 g, 57%). 1H NMR (CDCl3, 400 MHz) δ 8.17 (s, 1H), 7.20 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.50 (s, 2H), 3.79 (s, 3H), 3.59 (m, 4H), 3.48 (m, 4H), 3.35 (m, 2H), 3.30 (m, 2H), 1.49 (s, 9H). MS (APCI+) [M+H]+426.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]([CH2:77][CH3:78])([CH2:75][CH3:76])[O:73][B:72]([OH:79])[C:71]=2[CH:80]=1>CN(C=O)C>[CH2:77]([C:74]1([CH2:75][CH3:76])[O:73][B:72]([OH:79])[C:71]2[CH:80]=[C:67]([CH2:66][NH:65][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:26])[CH:68]=[CH:69][C:70]1=2)[CH3:78]
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CCC1(CC)OB(O)c2cc(CN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(CC)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(Cl)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.22 mmol) and DIPEA (114 mg, 0.88 mmol) in DMF (5.0 mL) can be stirred at rt for 5 min and then HATU (169 mg, 0.44 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-diethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (113 mg, 0.44 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified on column chromatography and prep-HPLC to provide the title compound.
Reaction SMILES: [Br-].[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[N:8]1[CH2:17][CH2:16][N+:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1.[Cl:18][C:19]1[N:20]=[C:21]([CH3:25])[NH:22][C:23]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:18][C:19]1[N:20]=[C:21]([CH3:25])[N:22]([CH2:12][CH2:13][CH2:14][CH2:15][N:11]2[CH2:10][CH2:9][N:8]([C:3]3[N:2]=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:17][CH2:16]2)[C:23]=1[Cl:24]
Reactant: c1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Reactant: Cc1nc(Cl)c(Cl)[nH]1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(Cl)n1CCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture of 450 g (1.5 moles) of 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4,5]decane bromide, 225 g (1.5 moles) of 4.5-dichloro-2-methylimidazole and 300 g (2.25 moles) of potassium carbonate in 2 l of dimethylformamide is heated to 130°-135° for 14 hours. The mixture is evaporated under vacuum, chloroform is added, the solution is washed with water, dried over sodium sulfate and evaporated under vacuum, and 503 g (91%) of 4,5-dichloro-2-methyl-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-imidazole are obtained in liquid form.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][CH2:16][CH2:17][CH2:18]I.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[CH2:18][CH2:17][CH2:16][Cl:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CC1CN2CCCCl
Temperature: 50 °C
Yield: 69.1 %

Procedure:
To a solution of 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.10 g, 0.50 mmol) in acetone (2 mL) was added 1-chloro-3-iodo-propane (0.10 g, 0.50 mmol, 1 eq) and K2CO3 (0.084 g, 0.60 mmol, 1.2 eq). The mixture was heated at 50° C. for 3 h and then cooled to r.t. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. Chromatography on silica gel by eluting with 5% MeOH/CH2Cl2 gave 0.095 g (69%) of 5-(3-chloro-propyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a yellowish oil. 1H NMR (300 MHz, CDCl3): δ 4.20 (m, 1H), 3.58 (m, 2H), 3.46 (m, 2H), 3.12 (m, 1H), 2.86 (m, 1H), 2.62 (m, 3H), 1.82 (m, 3H), 1.66 (m, 1H), 1.41 (s, 9H).