Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[CH:14]=[C:13]([N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])[C:12]([F:26])=[CH:11][C:10]=1[Cl:27])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1CCN2C(=NCCC2)CC1.O>O1CCCC1>[Cl:27][C:10]1[CH:11]=[C:12]([F:26])[C:13]([N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])=[CH:14][C:9]=1[CH:8]=[CH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)Cc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
In 20 ml of tetrahydofuran was dissolved 1.23 g of ethyl 2-chloro-3-(2-chloro-4-fluoro-5-phthalimidophenyl)propionate, and 0.69 g of 1,8-diazabicyclo[5.4.0]-7-undecene was slowly added thereto dropwise. After the addition, the stirring was continued at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to give 0.78 g of the title compound (No. 17 of Table 2).
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([F:18])[CH:12]=2)[CH:7]=[N:6][CH:5]=1.[CH3:20][NH2:21]>CO>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:8]2[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([NH:21][CH3:20])=[O:19])=[CH:12][C:13]=1[F:18]
Reactant: COC(=O)c1cncc(Oc2ccc(N)c(F)c2)c1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cncc(Oc2ccc(N)c(F)c2)c1
Temperature: 40 °C
Yield: 80.2 %

Procedure:
To a solution of 5-(4-amino-3-fluorophenoxy)nicotinic acid methyl ester (0.50 g, 1.91 mmol) in MeOH (2 mL) was added methylamine (0.63 g, 19.1 mmol, 2.0 M in MeOH). The reaction flask was sealed and heated at 40° C. for 4 h. Solvent was removed under reduced pressure, and the crude product was purified by column chromatography eluted with 5% MeOH/CH2Cl2 to give the 0.4 g (80%) of the title compound. 1H-NMR (DMSO-d6) δ 8.65 (d, J=1.8 Hz, 1H), 8.62 to 8.60 (m, 1H), 7.54 to 7.52 (m, 1H), 6.94 (dd, J=2.7, 12.0 Hz, 1H), 6.81 to 6.67 (m, 3H), 5.10 (s, 2H), 2.72 (d, J=2.4 Hz, 3H); MS LC-MS [M+H]+=262.2, RT=0.27 min.
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]([C:14]1[C:15]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:21][S:20][C:16]=2[N:17]=[CH:18][N:19]=1)[CH2:11][CH:12]=[CH2:13].[OH-:30].[Na+].OO>O1CCCC1.C(OCC)(=O)C.C(O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]2[C:15]3[C:14]([CH2:10][CH2:11][CH2:12][CH2:13][OH:30])=[N:19][CH:18]=[N:17][C:16]=3[S:20][CH:21]=2)=[CH:28][CH:27]=1
Reactant: C=CCCc1ncnc2scc(-c3ccc(F)cc3)c12
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCCCc1ncnc2scc(-c3ccc(F)cc3)c12
Temperature: 50 °C
Yield: 47 %

Procedure:
9-BBN (0.236 g, 0.00193 mol) in tetrahydrofuran (5.00 mL) was treated with 4-but-3-en-1-yl-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (0.500 g, 0.00176 mol) in tetrahydrofuran (3.0 mL) at 50° C. for 1 h. Ethanol (1.0 mL), 6 N sodium hydroxide (0.33 mL) and 30% hydrogen peroxide (0.67 mL) were then added successively and the resulting mixture was maintained at 50° C. for 1 h. The reaction was then cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with sodium bicarbonate (2×30 mL). The organic layers were combined, concentrated and purified by column chromatography over silica gel (using ethyl acetate/hexane 1:5-1:1 as an eluent) to afford 4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butan-1-ol as a white solid in 47% yield.
Reaction SMILES: [CH:1](N(C(C)C)CC)(C)[CH3:2].[C:10]1([CH3:30])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[NH:18][CH:19]=[N:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=1[CH3:29].[Cl:31]C(Cl)C>>[Cl-:31].[C:26]1([CH3:27])[CH:25]=[C:24]([CH3:28])[CH:23]=[C:22]([CH3:29])[C:21]=1[NH+:20]1[CH2:2][CH2:1][N:18]([C:11]2[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[CH3:30])[CH2:19]1
Reactant: CC(Cl)Cl
Reactant: Cc1cc(C)c(N=CNc2c(C)cc(C)cc2C)c(C)c1
Reactant: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(N2CC[NH+](c3c(C)cc(C)cc3C)C2)c(C)c1
Product: [Cl-]
Temperature: 120 °C
Yield: 91.2 %

Procedure:
According to method A1, diisopropylethylamine (0.34 mL, 1.96 mmol) was added to a stirred solution of N,N′-dimesitylformamidine (0.5 g, 1.78 mmol) and dichloroethane (1.36 mL, 17.8 mmol) in a schlenk tube. The tube was evacuated until solvent began to bubble and then sealed and heated to 120° C. for 24 hours. The reaction mixture was then cooled, added to toluene (40 mL) and then brought to reflux. While still hot, the precipitate was collected by vacuum filtration, washed with toluene (5 mL) and dried in vacuo to afford 1,3-dimesitylimidazolinium chloride (0.56 g, 92%) as a light peach powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](O)=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:54][CH:55]([F:66])[O:56][C:57]1[CH:64]=[CH:63][C:60]([CH2:61][NH2:62])=[CH:59][C:58]=1[F:65]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](=[O:29])[NH:62][CH2:61][C:60]2[CH:63]=[CH:64][C:57]([O:56][CH:55]([F:54])[F:66])=[C:58]([F:65])[CH:59]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)O)C1
Reactant: NCc1ccc(OC(F)F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)NCc2ccc(OC(F)F)c(F)c2)C1
Yield: 109.2 %

Procedure:
To a solution of the compound (1.83 g) obtained in Example 783, Step 2 in N,N-dimethylformamide (10 ml) were successively added, with stirring under ice-cooling, 1-hydroxybenzotriazole hydrate (677 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (847 mg) and a solution of 4-difluoromethoxy-3-fluorobenzylamine (806 mg) in N,N-dimethylformamide (3 ml). After stirring overnight at room temperature, the mixture was partitioned by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate, the combined organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give the title compound (2.76 g).
Reaction SMILES: [C:1]([C:4]([C:18]([O:20][CH3:21])=[O:19])([CH2:13][C:14]#[C:15][CH2:16][CH3:17])[CH:5]([CH:11]=O)[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]>C1C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[CH3:21][O:20][C:18]([C:4]1([CH2:13][C:14]#[C:15][CH2:16][CH3:17])[C:1](=[O:3])[CH:2]=[CH:11][CH:5]1[CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:19]
Reactant: CCC#CCC(C(C)=O)(C(=O)OC)C(C=O)CC(=O)OC
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCC#CCC1(C(=O)OC)C(=O)C=CC1CC(=O)OC

Procedure:
The compound (3) (500 mg) obtained above is dissolved in 200 ml of benzene containing 1 ml of acetic acid and 1 ml of piperidine, and the solution is refluxed for 6 hours. On completion of the reaction, the solvent is removed and the residue dissolved in ethyl acetate. The solution is washed with 10% hydrochloric acid and an aqueous solution of sodium bicarbonate and then dried. The product is concentrated, and the residue purified by a silica gel column, giving 5-methoxycarbonyl-4-methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (compound (1-a), R1 =R2 =CH3) in a yield of 81%, b.p. 110°-115° C./0.15 mm Hg.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])[CH:10]([CH3:24])[CH2:9]1)C1C=CC=CC=1.[Cl:25]C(OC(Cl)C)=O.CO>ClCCCl>[ClH:25].[CH3:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:16]=1/[CH:15]=[CH:14]/[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH3:24]
Reactant: Cc1cccc(C)c1/C=C/C1CCN(Cc2ccccc2)CC1C
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: Cc1cccc(C)c1/C=C/C1CCNCC1C
Product: Cl
Yield: 45.2 %

Procedure:
To a solution of 125 mg of 1-benzyl-4-[(E)-2-(2,6-dimethylphenyl)vinyl]-3-methylpiperidine in 3 ml of 1,2-dichloroethane, 139 mg of 1-chloroethyl chloroformate was added at ambient temperature. The mixture was heated under reflux for 1 hour. After cooling, 10 ml of methanol was added to the reaction mixture and the resulting mixture was heated under reflux for further 30 minutes. After cooling, the solvent was evaporated under reduced pressure. The residue was dissolved in 5 ml of ethyl acetate and the solution was filtered. To the filtrate was added 1 ml of 4N hydrochloric acid-ethyl acetate and the solvent was evaporated under reduced pressure. The residue was triturated in ethyl acetate. After filtration, the obtained solid was recrystallized from ethyl acetate-methanol to give 47 mg of 4-[(E)-2-(2,6-dimethylphenyl)vinyl]-3-methylpiperidine hydrochloride.
Reaction SMILES: [N-:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[K+].[CH2:7]([O:9][CH2:10][CH2:11]Br)[CH3:8]>C1COCC1>[CH2:7]([O:9][CH2:10][CH2:11][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:8]
Reactant: CCOCCBr
Reactant: c1c[n-]cn1
Agent: [K+]
Solvent: C1CCOC1
Product: CCOCCn1ccnc1

Procedure:
A Schlenk tube is charged with 5.5 g (52 mmol) of potassium imidazolide in 50 ml of THF. While stirring, 7.7 g (50 mmol) of 2-bromoethyl ethyl ether are added and the suspension is stirred for 4 hours, then warmed gently. After cooling, the reaction mixture is filtered and the solvent is removed. Distillation in a high vacuum gives 7a as a colorless liquid. The purity was checked by GC-MS. Only one fraction was observed here.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:22][C:23]1([CH3:27])[CH2:26][CH2:25][NH:24]1>>[CH3:22][C:23]1([CH3:27])[CH2:26][CH2:25][N:24]1[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: CC1(C)CCN1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Product: CC1(C)CCN1c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 100 °C
Yield: 59 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 93 mg, 0.329 mmol) and 2,2-dimethylazetidine (84 mg, 0.988 mmol; FCH Group, Chernigov, Ukraine), heating at 100° C. for 4 h. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-(3-(2,2-dimethylazetidin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (59% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.66 (s, 6H) 2.27 (t, J=7.53 Hz, 2H) 2.87 (t, J=6.85 Hz, 2H) 3.42 (td, J=6.75, 2.15 Hz, 2H) 4.14 (br. s., 2H) 6.95 (br. s., 1H) 7.12 (d, J=2.15 Hz, 1H) 7.36 (t, J=7.73 Hz, 1H) 7.64 (d, J=8.02 Hz, 1H) 7.95 (d, J=7.43 Hz, 1H) 8.35 (br. s., 1H) 12.09 (br. s., 1H). MS (ESI, pos. ion) m/z: 364.1 (M+1).
Reaction SMILES: C([C@H]1C[C@H](C2C=CC=C(Cl)C=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])C1=O)C=C.[C:35](#N)[CH3:36].I([O-])(=O)(=O)=O.[Na+].[C:44]([OH:56])(=[O:55])[CH2:45][C:46]([CH2:51][C:52](O)=O)([C:48]([OH:50])=O)O>O.CCOC(C)=O.O.[Ru](Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:28]([O:27][C:25](=[O:26])[C@@H:24]([N:6]1[C@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C@@H:52]([C:36]2[CH:35]=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH2:51][C@H:46]([CH2:45][C:44]([OH:56])=[O:55])[C:48]1=[O:50])[CH2:32][CH3:33])([CH3:29])([CH3:30])[CH3:31]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC#N
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC(C)(C)C)C1=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
To a rapidly stirring solution of 842 mg (1.67 mmol) of tert-butyl (2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate (Example 1, Step G) in a mixture of 7 mL of water, 5 mL of acetonitrile and 5 mL of CCl4 was added sodium periodate (1.43 g, 6.70 mmol), followed by ruthenium(III) chloride hydrate (37.8 mg, 0.168 mmol). After being stirred vigorously for 18 h, the reaction was acidified (10% citric acid) and diluted with EtOAc. The reaction mixture was filtered through celite and the filtrate was extracted with EtOAc. The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 60 to 80% acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O)=[O:4].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.[CH2:22]=[C:23]=[O:24]>C1(C)C=CC=CC=1>[C:23]([C:5](=[C:6]([NH:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:3]([O:2][CH3:1])=[O:4])(=[O:24])[CH3:22]
Reactant: NCc1ccccc1
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: C=C=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CC(NCc1ccccc1)=C(C(C)=O)C(=O)OC
Temperature: 25 °C

Procedure:
Dimethyl acetonedicarboxylate (50 g; 0.29 mmole) was dissolved in toluene (150 ml), and benzylamine (32.2 g; 0.3 mmole) was added thereto. The resultant mixture was heated under reflux for 30 minutes while elimination of water and then cooled to room temperature. Gaseous ketene was introduced therein. The precipitated crystals were collected by filtration and recrystallized from ethanol to give dimethyl 2-acetyl-3-benzylamino-2-pentenedioate. M.P., 123.5°-124.0° C.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][C:24]([CH3:30])=[C:25]([CH2:27][CH2:28]O)[N:26]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(N(CC)CC)C.[CH3:38][NH:39][CH:40]([CH3:42])[CH3:41]>ClCCl.O1CCCC1>[CH:40]([N:39]([CH2:28][CH2:27][C:25]1[N:26]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:12]=[CH:11][C:10]([S:7]([CH3:6])(=[O:9])=[O:8])=[CH:15][CH:14]=3)=[CH:21][CH:20]=2)[O:23][C:24]=1[CH3:30])[CH3:38])([CH3:42])[CH3:41]
Reactant: CNC(C)C
Reactant: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCN(C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
Add methanesulfonyl chloride (0.135 g, 0.935 mmol) to a cool (0° C.) solution of 2-[2-(4′-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethanol (0.257 g, 0.719 mmol) and triethylamine (0.182 g, 1.80 mmol) in dichloromethane (5 mL). Warm to room temperature and stir for 1 hour. Remove the solvents, transfer the residue to a sealed tube, add tetrahydrofuran (5 mL) and N-methyl-isopropylamine (0.526 g, 7.19 mmol), and heat at 60° C. overnight. Add dichloromethane and wash the crude organic material with saturated sodium chloride solution. Dry the organic layer over Na2SO4, filter, and concentrate. Purify on silica gel eluting with 5% ammoniated methanol in dichloromethane to give isopropyl-{2-[2-(4′-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-methyl-amine (0.056 g, 18%): mass spectrum (m/e): 413 (M+1). Treat the recovered material (0.056 g, 0.131 mmol) with 1N HCl (144 μL, 0.144 mmol) in ether, concentrate, and lyophilize to give the title compound (12.8 mg): MS (m/e): 413 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl.CCOC(C)=O>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCOCC1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCC(NC3CCOCC3)CC2)cc1
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
19 g of 4-amino-1-benzylpiperidine are placed in 50 ml of 1,2-dichloroethane under dry nitrogen and 10 g of tetrahydropyran-4-one in 20 ml of 1,2-dichloroethane are added; after stirring for 10 minutes, 29.6 g of NaBH(OAc)3 are added and the mixture is then stirred for one day. 10% Na2CO3 solution and EtOAc are added to the reaction medium and the phases are then separated by settling. The organic phase is washed with 10% Na2CO3 solution and then with saturated NaCl solution, and then dried over MgSO4 and evaporated under vacuum. 23.4 g of the expected compound are obtained. m.p.=60° C.
Reaction SMILES: [Si]([O:8][C@H:9]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([CH2:40][OH:41])[CH:34]=1)[CH2:10][NH:11][C@H:12]([CH3:32])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([NH:23][C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])=[O:22])[CH:17]=[CH:18][CH:19]=1)(C(C)(C)C)(C)C.ClCCl>CO>[NH3:11].[OH:8][C@H:9]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([CH2:40][OH:41])[CH:34]=1)[CH2:10][NH:11][C@H:12]([CH3:32])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([NH:23][C@@H:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH3:25])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: C[C@H](Cc1cccc(CC(=O)N[C@H](C)c2ccccc2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Solvent: ClCCl
Solvent: CO
Product: C[C@H](Cc1cccc(CC(=O)N[C@H](C)c2ccccc2)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Product: N

Procedure:
Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(1R)-1 -phenylethyl]acetamide (Preparation 21) according to the method for example 3 using dichloromethane:methanol: 880 ammonia (90:10:1 by volume) as the column eluent to give the title compound as a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]Br)=[CH:4][CH:3]=1.[CH3:11][NH2:12].[CH3:13]O>>[CH3:11][N:12]([CH3:13])[CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CO
Reactant: Oc1ccc(CCBr)cc1
Reactant: CN
Product: CN(C)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To 250 mg of 4-hydroxyphenethyl bromide in a round-bottomed flask, a 10 M excess of methylamine (6.22 mL of 2M in MeOH) was added and the solution was stirred at r.t. overnight. After filtration, the solvent was evaporated and gave the product in crystalline form in 92% yield, 0.23 g, light yellow. m.p.: 73-76° C. TLC (EtAc:MeOH, 9:1 v/v): RF=0.1. 1H NMR, δ: 9.43 (s, 1H), 7.12 (d, 2H), 6.70 (d, 2H), 2.74 (m, 4H), 2.30 (s, 6H). 13C NMR, δ: 167.5, 134.3, 130.2, 115.6, 60.6, 45.9, 32.4. Anal. calcd for C10H15NO: C, 72.69; H, 9.15; N, 8.48%. Found; C, 72.60; H, 9.30; N, 8.40%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].Cl[C:16]1[N:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][CH:17]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:16]1[N:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1cccc(Cl)n1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1COc1cccc(C#N)n1
Temperature: 50 °C
Yield: 24 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (189 mg, 1.0 mmol) and 6-chloropyridine-2-carbonitrile (150 mg, 1.0 mmol) in toluene (10 mL) was added sodium hydride (55% dispersion in mineral oil, 100 mg, 2.0 mmol) and the mixture heated at 50° C. for 6 h. Then 18-crown-6 (18 mg) was added and the mixture heated at 100° C. overnight. The mixture was then diluted with ethyl acetate and washed with water. The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded the title compound (70 mg, 24%) as a white solid after trituration with diisopropylether. MS: m/e=292.0 [M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14]>C(O)C>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13](=[N:2][OH:3])[NH2:14]
Reactant: N#Cc1ccccc1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=NO)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 32 g (0.46 moles) hydroxylamine hydrochloride and 49 g (0.46 moles) sodium carbonate in ethanol (about 200 ml) was stirred at room temperature for several minutes; then, 52.4 g (0.381 moles) chlorobenzonitrile was added slowly. The reaction mixture was heated to reflux and allowed to reflux about 6 hours. The reaction mixture was cooled at room temperature and suction-filtered. The solids were washed with acetone. The acetone washings were combined with the filtrate; the combined filtrate-washings were stripped. Acetone (about 200 ml) was added to the residue; the resulting mixture was allowed to sit overnight at room temperature. The mixture was filtered. The filtrate was stripped to give the crude product which was washed with hexane and ethyl ether, suction-filtered, and then air-dried to give the above-identified product as an off-white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.C([O-])(O)=O.[Na+].O.Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>C(O)C>[CH2:16]([O:15][C:13]([N:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:14])[CH:17]=[CH2:18]
Reactant: C1=CCNC1
Reactant: C=CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCOC(=O)N1CC=CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a solution of 3-pyrroline (3.5 gms) in ethanol (20 mL) was added ~25 mL saturated aq. NaHCO3 and enough water to allow rapid stirring. The mixture was cooled to 10° C. and allyl chloroformate (5.92 mL) was slowly added via pressure equalized addition funnel. The mixture was removed from ice bath and allowed to stir at room temperature for 2 hours. Product was extracted into Et2O (3×150 mL). The organic phase was washed with water (2×50 mL), dried (MgSO4) and solvent was evaporated at reduced pressure. Purification on silica (Et2O) afforded pure title compound.