Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39](C=O)[CH:38]=4)[C:33]([F:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.[C:54](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:47][N:48]5[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]5)[CH:38]=4)[C:33]([F:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:24][CH2:25]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(F)c(-c2cccc(C=O)c2)c1)C(=O)C1(C(N)=O)CC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(F)c(-c2cccc(CN3CCN(C)CC3)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A mixture of N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (50 mg, 0.080 mmol), 1-methylpiperazine (7.99 mg, 0.080 mmol), sodium triacetoxyborohydride (33.8 mg, 0.160 mmol) and acetic acid (5.48 μL, 0.096 mmol) in DCM (3 mL) was stirred at room temperature over the weekend. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give the crude residue. It was purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({6-fluoro-3′-[(4-methyl-1-piperazinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide as a solid (28 mg, 49.4%). LC-MS m/z 712 (M+H)+, 0.85 min (ret time); 1H NMR (400 MHz, DMSO-d6) δ 1.19 (t, J=7.53 Hz, 3H) 1.28-1.36 (m, 7H) 1.45-1.51 (m, 2H) 1.84-1.91 (m, 2H) 2.15 (s, 3H) 2.32-2.35 (m, 8H) 2.83 (q, J=7.53 Hz, 2H) 3.48-3.56 (m, 4H) 3.80-3.86 (m, 2H) 4.03-4.10 (m, 1H) 4.27-4.35 (m, 4H) 4.38 (d, J=6.02 Hz, 2H) 6.74 (d, J=7.78 Hz, 1H) 7.19-7.26 (m, 2H) 7.28-7.49 (m, 5H) 7.99 (s, 1H) 8.48 (t, J=5.77 Hz, 1H) 9.02 (t, J=5.77 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:11][CH3:12])=[O:10])[CH:4]=1)=[O:2].O1CCC[CH2:14]1.C[Mg]Br.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[OH:2][CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:11][CH3:12])=[O:10])[CH:4]=1)[CH3:14]
Reactant: C1CCOC1
Reactant: CNC(=O)c1cc(C=O)ccn1
Agent: C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(C(C)O)ccn1
Reaction time: 1 h

Procedure:
At 0° C. and under argon, 393 mg (2.394 mmol) of 4-formyl-N-methylpyridine-2-carboxamide Example 42A were initially charged in 66 ml abs. tetrahydrofuran. At 0° C., 343 mg (2.873 mmol) of methylmagnesium bromide [1.4 mol in toluene/tetrahydrofuran 3/1] were added dropwise, and the reaction solution was stirred at this temperature for 1 h. 200 μl of semisaturated aqueous sodium bicarbonate solution and 200 ml of ethyl acetate were added to the reaction solution. The precipitate was filtered off and washed with ethyl acetate. The filtrate was evaporated.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34]CC3C=CC=CC=3)[C:29]=2[O:42]CC2C=CC=CC=2)[CH:20]=1)[C:15]([OH:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H][H]>[Pd].C1COCC1>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[C:29]=2[OH:42])[CH:20]=1)[C:15]([OH:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(O)c2O)cc(C(=O)O)c1
Reaction time: 2.5 h
Yield: 91.1 %

Procedure:
A mixture of 1.7 g of 3-(decyloxy)-5-[[6-[2,3-bis(phenylmethoxy) phenyl]hexyl]oxy]benzoic acid and 0.3 g of 10% palladium on carbon in 75 ml of THF was stirred in a hydrogen atmosphere until uptake ceased after 2.5 hours. The usual workup followed by trituration of the crude product from hexane and filtration gave 1.13 g (91% yield, mp 86°-88°) of 3-(decyloxy)-5-[[6-(2,3-dihydroxyphenyl)hexyl]oxy]benzoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][N:18]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[N:6]=[CH:7][C:2]([CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][N:18]2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:3][CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: C1=NCCc2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-2-(trifluoromethyl)pyridine (258 mg, 1144 μmol) in THF (5 mL) at 0° C. was added isopropylmagnesium chloride (572 μL, 1144 μmmol) and the red/brown solution was stirred 2 h under N2. To a solution of 3,4-dihydroisoquinoline (75 mg, 572 μmol) in THF (2 mL) at 0° C. was added benzyl chloroformate (90 μL, 629 μmol) and the reaction was warmed to RT and stirred 15 min. The solution of Grignard reagent was added to the iminium salt and the reaction warmed to RT and stirred 1 h. The reaction was quenched with saturated NH4Cl (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated to give a yellow oil. Purification by ISCO (12 g SiO2, 0-50% EtOAc/hexane) gives benzyl 1-(6-(trifluoromethyl)-pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a yellow oil.
Reaction SMILES: I[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[N:12][CH:11]=[CH:10]3)=[CH:5][N:6]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=1.CN1C(=O)CCC1.CO>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:2]2[O:3][C:4]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[CH:13]=[N:12][CH:11]=[CH:10]4)=[CH:5][N:6]=2)=[CH:21][CH:20]=1
Reactant: Ic1ncc(-c2ccc3cnccc3c2)o1
Reactant: COc1ccc(CN)cc1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CNc2ncc(-c3ccc4cnccc4c3)o2)cc1
Temperature: 165 °C
Yield: 136.3 %

Procedure:
A glass microwave reaction vessel was charged with 6-(2-iodooxazol-5-yl)isoquinoline (0.10 g, 310 μmol), (4-methoxyphenyl)methanamine (0.28 mL, 217 μmol) and NMP (2.00 mL). The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 165° C. for 10 minutes. The residual product was adsorbed onto a plug of silica gel and chromatographed through two stacked Redi-Sep® pre-packed silica gel column (12 g), eluting with a gradient of 1% to 10% of 2 M NH3.MeOH in DCM to provide N-(4-methoxybenzyl)-5-(isoquinolin-6-yl)oxazol-2-amine (98 mg, 95% yield). LCMS (API-ES) m/z (%): 332.1 (100%, M++H); 1H NMR (400 MHz, MeOH-d4) δ ppm 9.12 (s, 1H) 8.38 (d, J=5.87 Hz, 1H) 8.04 (d, J=8.80 Hz, 1H) 7.94 (s, 1H) 7.84 (dd, J=8.61, 1.56 Hz, 1H) 7.76 (d, J=5.87 Hz, 1H) 7.42 (s, 1H) 7.33 (d, J=8.80 Hz, 2H) 6.90 (d, J=8.61 Hz, 2H) 4.47 (s, 2H) 3.77 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[C:4]([CH3:10])[CH:3]=1.[CH2:11](O)[CH3:12]>S(Cl)(Cl)=O>[CH2:11]([O:8][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][C:4]=1[CH3:10])=[O:9])[CH3:12]
Reactant: CCO
Reactant: Cc1cc(Br)sc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1sc(Br)cc1C
Temperature: 0 °C

Procedure:
5-Bromo-3-methyl-thiophene-2-carboxylic acid (example 1.b, 10.0 g, 45.2 mmol) was suspended in 40 mL of thionyl chloride. The mixture was heated at reflux temperature for 1 hour and then cooled to 0° C. with an external ice bath. Cold ethyl alcohol (150 mL) was carefully added, and the solution was heated at reflux temperature for 16 hours. Under reduced pressure, the solution was concentrated to ca. one third of the original volume and then diluted with ethyl acetate and washed successively twice with saturated sodium bicarbonate solution, and once with brine. The organic fractions were dried over anhydrous sodium sulfate and concentrated to 7.9 g of a yellow oil: 1H NMR (CDCl3, 200 MHz): δ=6.87 (s, 1H), 4.34-4.23 (q, 1H, J=7.0 Hz), 2.50 (s, 3H), 1.39-1.32 (t, 3H, J=7.0 Hz).
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].[CH:14]1([O:19][C:20]2[CH:21]=[C:22](/[CH:28]=[CH:29]/C=O)[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH2:18][CH2:17][CH2:16][CH2:15]1.O1CCC[CH2:33]1>>[CH:14]1([O:19][C:20]2[CH:21]=[C:22](/[CH:28]=[CH:29]/[CH:5]=[CH:4]/[C:6]([O:8][CH3:33])=[O:7])[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: COc1ccc(/C=C/C=O)cc1OC1CCCC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)/C=C/C=C/c1ccc(OC)c(OC2CCCC2)c1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 0.26 g (5.41 mmol) of a 50% oil suspension of sodium hydride (previously washed with three, 10 mL portions of hexane) in 200 mL of dry tetrahydrofuran under a nitrogen atmosphere was added dropwise at room temperature 0.8 mL (4.94 mmol) of trimethylphosphonoacetate in 100 mL of dry tetrahydrofuran over a 20 minute period. The white suspension was stirred for an additional 16 hours after which time 0.99 g (4.02 mmol) of 3-(3-cyclopentoxy-4-methoxyphenyl)-E-propene-1-aldehyde in 30 mL of dry tetrahydrofuran was added dropwise over a 5 minute period. The final reaction mixture was stirred for an additional 30 minutes after which time the mixture was quenched with 50 mL of saturated ammonium chloride. After separation of the solvent layers, the organic fraction was extracted with 30 mL of ethyl acetate and the combined organic fractions were dried over sodium sulfate and concentrated. Crystallization from hexane provided the desired, analytically pure product.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[CH2:13][N:14]1[CH2:18][CH2:17][C:16]([CH2:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][C:27]=2[F:38])([C:19]([O:21]C)=[O:20])[CH2:15]1.Cl>O1CCOCC1.O.ClCCl>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[CH2:13][N:14]1[CH2:18][CH2:17][C:16]([CH2:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][C:27]=2[F:38])([C:19]([OH:21])=[O:20])[CH2:15]1
Reactant: COC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(C/C=C/c2cc(F)ccc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(C/C=C/c4cc(F)ccc4F)C3)c2c1

Procedure:
1.137 cm3 of a 5 N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 0.0675 g (0.135 mmol) of the enantiomer B (dextrorotatory) of methyl 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate in solution in 3 cm3 of dioxane. After stirring under reflux for 48 hours, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 2 cm3 of water and 5 cm3 of dichloromethane. The aqueous phase is acidified with 1 N and then 0.1 N hydrochloric acid to a pH value of 7. The aqueous phase is extracted with twice 5 cm3 of dichloromethane. The organic phases are combined, washed with 5 cm3 of water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.035 g of the enantiomer B of 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (absolute configuration not determined) in the form of a beige solid melting at 80–84° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>ClCCl.N1C=CC=CC=1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCCCl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
A solution of 6-chlorohexan-1-ol (25.0 g, 0.183 mol) in dichloromethane (DCM) (166 ml) and pyridine (33 ml) was cooled to −5° C. Toluene-p-sulphonyl chloride (40.1 g, 0.210 mol) was slowly added to the stirred solution and left to react overnight. The reaction mixture was treated with ice (80 g) and left stirring for 1 h. The organic layer was washed with ice cold 2M-sulphuric acid and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by column chromatography [DCM] to give a white powder 40.20 g, 85%; mp 27-28° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.CO.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C[O-].[Na+]>C1CCCCC1.O>[C:15]1([C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: O=C1CCCCC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCCCC1
Product: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
A 12 L round-bottomed flask was equipped with a reflux condenser and a mechanical stirrer, and the system was purged with nitrogen gas. 6-Indole carboxylic acid (300.00 g, 1.86 mole, 3 equivalents) was charged into the flask, followed by MeOH (5.5 L). After stirring for 10 min at room temperature, cyclohexanone (579 mL, 5.58 mole) was added. Methanolic sodium methoxide (25% w/w, 2.6 L, 11.37 mole, 6.1 equivalents) was added in portions over 10 min. The mixture was then refluxed for 48 h. After cooling to room temperature, water (4 L) was added and methanol removed under reduced pressure. The residual aqueous phase was acidified to pH 1 with concentrated HCl (˜1.2 L). The resulting yellowish precipitate was collected by filtration, washed with water and dried under vacuum at 50° C. The desired cyclohexane derivative was obtained as a beige solid (451.0 g, 100% yield).
Reaction SMILES: [C:1]([CH:4]([CH:6]([C:8]([O-:10])=[O:9])O)O)([O-])=O.[K+].[K+].[C:13](O)(=O)[CH:14]([CH:16]([C:18](O)=O)[OH:17])O>CC(C)=O>[C:8]([O:10][CH2:13][CH3:14])(=[O:9])[CH3:6].[CH:16]([O:17][CH:4]([CH3:6])[CH3:1])([CH3:18])[CH3:14]
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)OC(C)C
Product: CCOC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.1 g of crude N-(N-carbobenzoxy-DL-α-hydroxyalanyl)-L-phenylalanyl-L-proline p-nitrophenyl ester obtained in step hi), hii) or hiii) below, in 300 ml acetone, is treated with a 10% (w/v) potassium tartrate solution (having pH = 7.9). The reaction mixture is stirred for 18 hours at room temperature, and worked up by the addition of 10% (w/v) tartaric acid solution until the reaction mixture is at a pH of 5 and extraction with methylene chloride. The product obtained on concentration is crystallized from ethyl acetate or an ethyl acetate/diisopropyl ether mixture (3:1; v/v) yielding, after drying at 90° in a high vacuum, the aci-form of the title compound (M.Pt. 206°-208°; decomposition); [α]D20 = -28° (c = 0.5 in CH3OH).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14][NH:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>ClCCl>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14][N:13]2[C:31]([O:32][CH3:33])=[O:34])=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)C1CCNC(c2ccc(C(C)(C)C)cc2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.6 %

Procedure:
To a suspension of methyl 2-(4-tert-butylphenyl)piperidine-4-carboxylate hydrochloride (9.66 g, 30.98 mmol) in dichloromethane (100 mL) was added DIPEA (12 mL, 68.89 mmol). The reaction mixture was cooled in an ice-bath and methyl carbonochloridate (2.8 mL, 35.56 mmol) was added dropwise over 5 min. The reaction mixture was stirred for 18 h at room temperature and washed with 3.8 N HCl. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Dimethyl 2-(4-tert-butylphenyl)piperidine-1,4-dicarboxylate (10.6 g, quant.) was isolated as a dark brown oil. MS m/z 334 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]=[O:15])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Mg]Br>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([OH:15])[CH3:18])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC=O)COC1(C)C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of (S)-2,2-dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid t-butyl ester (2.05 g, 8.43 mmol) in dry tetrahydrofuran (25 mL) was added 1.4M methyl magnesium bromide in diethyl ether (6.02 mL) at −78° C. The mixture was stirred at −78° C. for 30 min and then warmed to −5° C. The mixture was extracted with diethyl ether and ammonium chloride solution. The organic layer was dried and concentrated. The crude mixture was purified by ISCO flash chromatography (0 to 60% ethyl acetate/hexanes) to give two fractions. The first fraction afforded (S)-4-((S)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester as a colorless oil (870 mg): 1H NMR (300 MHz, CDCl3) δ ppm 1.20 (d, J=6.0 Hz, 3H), 1.42-1.60 (m, 1H), 1.50 (s, 12H), 1.55 (s, 3H), 1.68-1.88 (m, 1H), 3.66 (d, J=8.8 Hz, 1H), 3.69-3.80 (m, 1H), 3.94-4.08 (m, 1H), 4.17-4.30 (m, 1H), 4.62 (br. s., 1H); The second fraction afforded (S)-4-((R)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester as a white solid (740 mg): 1H NMR (300 MHz, CDCl3) δ ppm 1.22 (d, J=6.0 Hz, 3H), 1.49 (s, 12H), 1.58 (br. s., 3H), 1.75-1.90 (m, 2H), 2.56 (br. s., 1H), 3.75-3.93 (m, 2H), 3.95-4.05 (m, 1H), 4.03-4.20 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[N:14][N:4]2[N:3]=1.[CH3:15][NH2:16]>CO>[CH3:15][NH:16][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[N:14][N:4]2[N:3]=1
Reactant: CN
Reactant: Clc1nn2nnnc2c2c1CCCC2
Solvent: CO
Product: CNc1nn2nnnc2c2c1CCCC2

Procedure:
A mixture of 6.0 g of 6-chloro-7,8,9,10-tetrahydrotetrazolo[5,1-a]phthalazine and 125 ml of 40% aqueous methylamine in 15 ml of methanol was heated under reflux for 3 hours. The reaction mixture was then cooled and the crystalline solid present was separated by filtration. It was recrystallized from a mixture of dimethylsulfoxide and water to give 6-methylamino-7,8,9,10-tetrahydrotetrazolo[5,1-a]phthalazine melting at about 318° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[C:21]([CH:25]=O)[CH:20]=[CH:19][C:18]=2[CH:17]=[CH:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[F:13][C:2]([F:1])([F:12])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][CH2:25][C:21]2[N:22]=[C:23]3[C:18]([CH:17]=[CH:16][C:15](=[O:14])[NH:24]3)=[CH:19][CH:20]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=Cc1ccc2ccc(=O)[nH]c2n1
Reactant: NC1CCN(C(=O)C(F)(F)F)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: O=C(N1CCC(NCc2ccc3ccc(=O)[nH]c3n2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61.7 %

Procedure:
To a solution of 0.53 g of 1-(trifluoroacetyl)piperidin-4-amine in 100 mL of dichloromethane, 0.47 g of 7-oxo-7,8-dihydro-1,8-naphthyridine-2-carbaldehyde and 0.16 mL of acetic acid were added, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was added with 0.86 g of sodium triacetoxyborohydride and stirred at the same temperature for 5 hours. Thereto were added water, a saturated aqueous sodium hydrogen carbonate solution and chloroform, the organic layer was separated, and the aqueous layer was extracted with chloroform. Sodium chloride was further added to the aqueous layer, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=20:1 to obtain 0.59 g of 7-(((1-(trifluoroacetyl)piperidin-4-yl)amino)methyl)-1,8-naphthyridin-2(1H)-one as a light orange foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH3:9][NH2:10].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][CH3:9])=[N:6][CH:7]=1
Reactant: CN
Reactant: Fc1ccc(Br)cn1
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc(Br)cn1
Yield: 24 %

Procedure:
A solution of 5-bromo-2-fluoropyridine (2.5 g, 14 mmol) in THF (50 mL) was stirred with a solution of methylamine in THF (c=2 mol/L) (35 mL, 70 mmol) at 23° C. for 16 h. Water was added and the mixture was extracted with ether, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a residue which was purified by silica gel column chromatography with heptane/ether, followed by trituration with heptane to give the title compound as a white solid (630 mg, 24%). MS (ISP) 187.1 [(M+H)+], 189.2 [(M+2+H)+].