Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C@H:4]([CH2:16][OH:17])[CH2:3]1.[H-].[Na+].S(OCC)(O[CH2:24][CH3:25])(=O)=O.O>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C@H:4]([CH2:16][O:17][CH2:24][CH3:25])[CH2:3]1
Reactant: CCOS(=O)(=O)OCC
Reactant: CN1CC[C@H](c2ccc(Cl)c(Cl)c2)[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC[C@@H]1CN(C)CC[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A solution of (3) (2.4 g, 8.6 mmol) in tetrahydrofuran (40 ml) was added 60% NaH (0.69 g, 17 mmol) and stirred at room temperature for one hour. Diethyl sulfate (1.4 ml, 11 mmol) was added and the reaction mixture stirred over night. Water was added and the reaction mixture was extracted with diethyl ether (3×40 ml). The combined organic phases was dried with magnesium sulfate and evaporated to dryness. Column chromatography, using a mixture of dichloromethane, methanol and ammonia (aq) (9:1:1%) yielded 1.5 g (56%) of product (9) (oil).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:21])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C(O[N:40]=O)CC(C)C>C1C=CC=CC=1>[NH:1]1[C:2]2[C:3](=[C:4]([O:5][CH:6]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]3)[CH:18]=[CH:19][CH:20]=2)[CH:21]=[N:40]1
Reactant: CC(C)CCON=O
Reactant: Cc1c(N)cccc1OC1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc3[nH]ncc23)C1
Temperature: 25 °C

Procedure:
A solution of t-butyl 3-(3-amino-2-methylphenoxy)pyrrolidin-1-Carboxylate (4.6 g, 15.4 mmol), potassium acetate (1.81 g, 18.5 mmol) and acetic anhydride (5.02 g, 49.2 mmol) in benzene is treated dropwise with isoamylnitrite (4.13 ml, 30.8 mmol), heated at reflux temperature overnight, cooled to room temperature and filtered. The filtercake is washed with benzene. The combined filtrates are concentrated to give a yellow oil residue. The residue is purified by chromatography (SiO2, 25% EtOAc in hexanes). The resultant oil is dissolved in ethanol, treated with 40% aqueous NaOH, heated at reflux temperature for 45 min, cooled with an ice-water bath, neutralized to pH 9 with concentrated HCl and concentrated in vacuo. The resulting aqueous mixture is extracted with EtOAc. The combined extracts are washed with water and brine, dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid, 2.6 g, mp 196-198° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:18][CH2:17][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[O:7][C:6]4[CH2:17][CH2:18][CH:3]([N:2]([CH3:1])[CH3:19])[CH2:4][C:5]=4[C:9]=3[CH:10]=2)=[O:16])[CH:22]=1
Reactant: CN(C)C1CCc2oc3ccc(C(=O)O)cc3c2C1
Reactant: Nc1cccnc1
Product: CN(C)C1CCc2oc3ccc(C(=O)Nc4cccnc4)cc3c2C1
Yield: 43.4 %

Procedure:
Beginning with 0.17 gm (0.57 mMol) N,N-dimethyl-8- carboxy-1,2,3,4-tetrahydro-2-dibenzofuranamine and 0.06 gm (0.63 mMol) 3-aminopyridine, 0.083 gm (44%) of the title compound were recovered as an off-white foam by the procedure described in Example 25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][N:13]1[C:17](=[O:18])C2=CC=CC=C2C1=O.[OH2:24].NN.Cl>CO>[C:4]([O:24][C:17](=[O:18])[NH:13][CH2:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:12])([CH3:5])[CH3:3]
Reactant: COc1ccc([N+](=O)[O-])cc1CN1C(=O)c2ccccc2C1=O
Reactant: O
Agent: Cl
Agent: NN
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
To a mixture of the compound (357 mg) obtained in Example 117 and methanol (10 ml), hydrazine monohydrate (0.06 ml) was added and stirred at room temperature for 3 h. The reaction mixture was made acidic by addition of 2 N HCl and washed with ethyl acetate. The aqueous layer was made alkaline by addition of a 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate; then, the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the resulting residue in dimethylformamide (10 ml), di-t-butyl dicarbonate (274 mg) and triethylamine (0.17 ml) were added and stirred at room temperature for 3 h. Water and 2 N HCl were added to the reaction mixture and extraction was performed with ethyl acetate; then, the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1) to give 62 mg of the titled compound (yield, 20%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: N#CCc1cccc(N)c1
Temperature: 22 °C
Reaction time: 48 h

Procedure:
To a solution of 3-nitro-phenyl-acetonitrile (3.20 g, 19.7 mmol) in MeOH (50 mL) was added Pd/C (10% wt, ˜50% H2O, 0.32 g) and the mixture was placed under H2 (80 psi) and stirred for 2 days at 22° C. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo to give crude product as a yellow oil. The residue was purified by silica gel chromatography (ISCO, elution with 0-10% ethyl acetate in hexanes) to give xix-l-1 (1.15 g, 44%): MS m/z=133 (M−H).
Reaction SMILES: Br[C:2]1[C:3](Cl)=NC(Cl)=N[CH:7]=1.[Br:10][C:11]1[C:12]([NH:18][CH:19]([CH:29]([CH3:31])[CH3:30])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Br:10][C:11]1[C:12]([NH:18][C@@H:19]([C:29]2[CH:31]=[CH:3][CH:2]=[CH:7][CH:30]=2)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Reactant: Clc1ncc(Br)c(Cl)n1
Product: CC(C)(C)OC(=O)NC[C@@H](Nc1nc(Cl)ncc1Br)c1ccccc1

Procedure:
Intermediate J was hydrogenated using 10% Pd/C under hydrogen at 50 psi in a pressure vessel to afford tert-butyl N-[(2S)-2-amino-2-phenyl-ethyl]carbamate which was then reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to afford tert-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-phenyl-ethyl]carbamate. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.32 (s, 9H) 3.29-3.50 (m, 2H) 5.12-5.24 (m, 1H) 7.10 (t, J=5.27 Hz, 1H) 7.21 (t, J=6.88 Hz, 1H) 7.26-7.34 (m, 4H) 7.89 (d, J=7.32 Hz, 1H) 8.24 (s, 1H). LCMS (ESI) 427 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]([CH3:38])[CH3:37])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]([CH3:38])[CH3:37])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CC(C)Oc1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OC(C)C)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-isopropoxy-pyridine.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[CH:14]=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32](O)=[O:33])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([NH:20][C:15]2[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]3[O:3][C:2]([CH3:21])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:5]=3[CH:14]=2)=[O:33])=[CH:26][CH:25]=1
Reactant: Cc1ccc(C2c3cc(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: COc1ccc(CCC(=O)O)cc1
Product: COc1ccc(CCC(=O)Nc2cc3c(c(C)c2C)OC(C)(C)C3c2ccc(C)cc2)cc1
Yield: 64 %

Procedure:
Using 2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine obtained Reference Example 139 and 3-(4-methoxyphenyl)propionic acid, the title compound was obtained in the same manner as in Reference Example 359.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[N:12]=[C:13]([CH2:16]O)[S:14][CH:15]=2)[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>ClCCl>[Br:24][CH2:16][C:13]1[S:14][CH:15]=[C:11]([C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:22])=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)[N:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)c1cc(-c2csc(CO)n2)cc(C(C)(C)C)c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(-c2csc(CBr)n2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Yield: 92 %

Procedure:
1.5 g (4.70 mmol) of intermediate 334.2, (2,6-ditert-butyl-4-[2-(hydroxymethyl)-1,3-thiazol-4-yl]phenol is dissolved in dichloromethane (30 ml). After adding CBr4 (2.02 g; 6.10 mmol), the reaction medium is cooled down to 0° C. PPh3 (1.48 g; 5.63 mmol) is added by fractions then the mixture is left to return to ambient temperature. The reaction medium is then poured into ice-cooled water before being extracted with dichloromethane. The organic phase is washed with salt water before being dried over magnesium sulphate, filtered and concentrated under vacuum. The expected product is obtained after chromatography on a silica column (eluent: 30% of ethyl acetate in heptane), in order to produce a brown oil with a yield of 92%. This product is sufficiently pure to be used directly in the following stage.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[CH:5]=[C:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]=1.[Li]CCCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C.Cl>C1COCC1.C(OCC)(=O)C>[CH2:13]([C:4]1[CH:3]=[C:2]([B:26]([OH:27])[OH:25])[C:10]2[O:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)Cc1cc(Br)c2c(c1)C(C)(C)CO2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cc1cc(B(O)O)c2c(c1)C(C)(C)CO2
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 49.6 %

Procedure:
To a mixture of 7-bromo-5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran (9.9 g, 34.96 mmol) in THF (50 mL) cooled to −78° C. under an atmosphere of argon was added n-BuLi (25.17 mL, 2.5 M, 62.93 mmol) dropwise. The reaction mixture was stirred for 5 minutes and triisopropylborate (24.2 mL, 104.87 mmol) was added dropwise. The mixture was stirred at −50° C. for 2 hours then warmed up to room temperature and stirred overnight at room temperature. 1.0 N HCl (100 mL) was slowly added to the reaction mixture. After 1 hour the mixture was diluted with ethyl acetate and the layers separated. The organic layer was further washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel (0 to 20% ethyl acetate in hexane) to give 4.3 g of 5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-boronic acid (46%). 1H NMR (300 MHz; CDCL3): 0.90 (d, J=6.6 Hz, 6H), 1.33 (s, 6H), 1.81 (m, 1H), 2.43 (d, J=7.5 Hz, 2H), 4.28 (s, 2H), 5.86 (br s, 2H), 6.98 (d, J=2.1 Hz, 1H), 7.33 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]1>C(O)(=O)C>[CH2:1]([N:15]1[CH2:16][CH2:17][CH:18]([CH2:21][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:19][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CC1CCNCC1)C(=O)OCC
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(CC1CCN(Cc2ccccc2)CC1)C(=O)OCC
Temperature: 62.5 °C
Reaction time: 12 h

Procedure:
Benzyl chloride (54.4 g) and sodium carbonate (149.4 g) were added to the solution of the acetic acid salt of diethyl (4-piperidylmethyl)malonate [XXIXb] from the previous step. The obtained slurry was stirred for 12 hours at 60-65° C. and evaporated under reduced pressure. Water was added to the residue and the obtained mixture was extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, passed through short silica gel column and evaporated under reduced pressure. The obtained residue was washed with hexanes and dried under reduced pressure to give diethyl (N-benzyl-4-piperidylmethyl)malonate [XXIIb].
Reaction SMILES: [C:1]1([C:7]2([N:13]3[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C>[C:1]1([C:7]2([N:13]3[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCN(C2(c3ccccc3)CCCCC2)CC1
Solvent: CC(=O)O
Product: O=C1CCN(C2(c3ccccc3)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1-(1 phenylcyclohexyl)-4 hydroxypiperidine was dissolved in 15 mL glacial acetic acid and 0.3 mL concentrated slufuric acid, and 1.9 mL Jones reagent (made from 26.72 g H2CrO4 and 23 mL H2SO4 diluted to 100 mL with water) was added dropwise. After stirring at room temperature for 20 minutes, 2 mL 2-propanol, Zn(Hg) (made from 1.5 g mossy zinc and 0.2 g mercuric chloride in 20 mL water and 0.25 mL concentrated hydrochloric acid at room temperature for 5 minutes), sodium citrate dihydrate (3.6 g) and 35 mL deionized water were added sequentially. After stirring the solution at room temperature for 30 minutes, the reaction was extracted with chloroform. The solvent was removed in vacuo. Distilled water was added and removed in vacuo. The residue was chromatographed on silica gel eluted with the appropriate mixture of methanol and chloroform to yield pure 1 (1 phenylcyclohexyl)-4-piperidone.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[N:5]1[CH2:17][CH2:18][N:19]1C(=O)C2=CC=CC=C2C1=O.NN>C(O)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[N:5]1[CH2:17][CH2:18][NH2:19]
Reactant: COCC1CCC(c2ccccc2OC)N1CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: COCC1CCC(c2ccccc2OC)N1CCN
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.9 %

Procedure:
To a solution of 2-methoxymethyl-5-(2-methoxyphenyl)-(2-phthalimidoethyl)-tetrahydropyrrole (333 mg, 0.85 mmol) in ethanol (5 mL) was added anhydrous hydrazine (80 μl, 2.5 mmol). The resulting suspension was stirred at room temperature for 3 days. The reaction mixture was filtered through Celite™, and the solid was washed with methanol (40 mL). The filtrate was concentrated in vacuo, the residue was triturated with CH2Cl2 (40 mL) and filtered to remove any remaining byproduct. The filtrated was again concentrated to afford the title compound as a light yellow oil (211 mg). MS m/z: 265 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[CH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)[CH2:10][CH2:9]1.Cl.[H][H]>O.[C].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=C1CCc2cc(C=CCCN3CCN(c4ccccc4Cl)CC3)ccc2N1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: O=C1CCc2cc(CCCCN3CCN(c4ccccc4Cl)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.37 Gram of 6-{4-[4-(2-chlorophenyl)-1-piperazinyl]-1-butenyl}-3,4-dihydrocarbostyril and 0.1 g of 10%-palladium carbon were suspended in 40 ml of water, then 0.2 ml of concentrated hydrochloric acid was added to the suspension and the mixture was catalytically hydrogenated under 5 atmospheric pressure of hydrogen gas at an ordinary temperature. The catalyst was removed by filtration and to the filtrate were added 10N-NaOH and ether and stirred at a room temperature for 30 minutes. The crystals thus precipitated were collected by filtration and recrystallized from isopropanol to obtain 6-{4-[4-(2-chlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril in colorless prism-like crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].C([O:17][C:18](=O)[C:19]([F:22])([F:21])[F:20])C>C(O)C>[F:20][C:19]([F:22])([F:21])[C:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[O:17]
Reactant: NCCCCCCCCCCCCO
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCO
Product: O=C(NCCCCCCCCCCCCO)C(F)(F)F
Yield: 98.2 %

Procedure:
An ethanol solution (100 ml) of 12-aminododecanol (4.81 g, 23.9 mmol) and trifluoroacetic acid ethyl ester (6.79 g, 47.8 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 12-trifluoroacetamidododecanol (1) (6.98 g, q.) as a colorless syrup.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:16]=[N:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH:23](O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[C:10]=1[C:11]#[N:12].C([SiH](CC)CC)C>ClCCl>[CH2:23]([C:20]1[CH:19]=[CH:18][C:17]([C:13]2[CH:14]=[N:15][CH:16]=[C:9]([Cl:8])[C:10]=2[C:11]#[N:12])=[CH:22][CH:21]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N#Cc1c(Cl)cncc1-c1ccc(C(O)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c(Cl)cncc1-c1ccc(Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Trifluoroacetic acid (5 mL, 64.9 mmol) was added to a solution of 3-chloro-5-(4-(hydroxy(phenyl)methyl)phenyl)isonicotinonitrile (327 mg, 0.816 mmol, 80% pure) and triethylsilane (5 mL, 31.3 mmol) in dichloromethane (10 mL). After 1 h at room temperature, the mixture was concentrated, quenched with saturated sodium bicarbonate (30 mL) and extracted with dichloromethane (3×15 mL). The combined extracts were dried (MgSO4) and concentrated. Silica gel chromatography, loading with toluene and eluting with 10-30% ethyl acetate in hexanes, gave 3-(4-benzylphenyl)-5-chloroisonicotinonitrile as colorless liquid (195.2 mg, 79% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (1H, s), 8.68 (1H, s), 7.45-7.58 (2H, m), 7.28-7.43 (4H, m), 7.15-7.28 (3H, m), 4.07 (2H, s). MS (ES+) m/z: 305 (M−H2O+H); LC retention time: 4.391 min (analytical HPLC Method A).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=O.S(Cl)([Cl:13])=O>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][Cl:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cncc(Br)c1
Product: ClCc1cncc(Br)c1

Procedure:
A solution of 5-bromonicotinic acid (4 g, 0.02 mol) in thionyl chloride (25 mL) was heated under reflux for 4 h. The excess thionyl chloride was removed under reduced pressure to provide 5-bromonicotinyl chloride which was used without further purification. To 5-bromonicotinyl chloride (3.5 g, 13.6 mmol) was added glycine ethylester (2.1 g, 20.3 mmol) and diisopropyl ethyl amine (2.6 g, 20.1 mmol) in THF (70 mL) and the reaction mixture stirred at RT for 16 h. The reaction mixture was diluted with EtOAc and washed with brine solution. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure and the residue was purified by silica gel column chromatography using 25% EtOAc in hexane to provide ethyl 2-(5-bromonicotinamido)acetate 1.2 g (33%) as a brown solid. LCMS Method T: retention time 1.28 min; [M+1]=288.2
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=3[CH3:23])[CH2:32][CH2:33]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cccc(C)c2C)CC1
Yield: 83 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[N:7]([CH3:21])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reactant: CI
Solvent: CN(C)C=O
Product: CCCc1ccc(N(C)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.6 %

Procedure:
To a solution of (3-nitro-4-propyl-phenyl)-carbamic acid tert-butyl ester (200 mg, 0.71 mmol) in DMF (5 mL) was added Ag2O (1.0 g, 6.0 mmol) followed by methyl iodide (0.20 mL, 3.2 mmol). The resulting suspension was stirred at room temperature for 18 h and filtered through a pad of Celite. The filter cake was washed with CH2Cl2 (10 mL). The filtrate was concentrated in vacuo. The crude oil was purified by column chromatography (0-10% CH2Cl2-MeOH) to afford methyl-(3-nitro-4-propyl-phenyl)-carbamic acid tert-butyl ester as a yellow oil (110 mg, 52%). 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, J=2.2 Hz, 1H), 7.42 (dd, J=8.2, 2.2 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 3.27 (s, 3H), 2.81 (t, J=7.7 Hz, 2H), 1.66 (m, 2H), 1.61 (s, 9H), 0.97 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[CH3:37]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[C:29]([CH3:37])[CH:30]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: Cc1cc(B(O)O)ccc1F
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(F)c(C)c2)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-fluoro-3-methyl-phenylboronic acid, 5-(4-fluoro-3-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=48%).