Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH2:14])[CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH:14][C:15](=[O:17])[CH3:16])[CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:3]=1
Reactant: COCCCC(N)c1cc(Br)ccn1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCCCC(NC(C)=O)c1cc(Br)ccn1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 32.0 g of 1-(4-bromopyridin-2-yl)-4-methoxybutylamine in 150 ml of glacial acetic acid is mixed with 37 ml of acetic anhydride. The reaction solution is stirred at 50° C. for 30 minutes and then diluted with ethyl acetate. It is basified with 2M sodium hydroxide solution, and the phases are separated. The aqueous phase is extracted with ethyl acetate (2×). The combined organic phases are evaporated. The title compound is obtained as a yellowish solid from the residue by flash chromatography (SiO2 60 F). Rf=0.38 (EtOAc-methanol 9:1); Rt=2.33 (Gradient I).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:13](Cl)(=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.Cl>N1C=CC=CC=1>[CH3:1][N:2]([C:13](=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(N(C)C(=O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-methylaminobenzoate (1.0 g, 6.05 mmol) in anhydrous pyridine (20 mL) was added dropwise hydrocinnamoyl chloride (1080 μL) at rt. After 16 hrs water (5 mL) was added and the resulting mixture was stirred for 1 hr at rt. The resulting mixture was poured into water (300 mL) and HCl (5 N, 50 mL) was added. The compound was extracted with AcOEt (2×300 mL) and washed with a saturated aqueous solution of NaHCO3 (150 mL). The combined organic layers were dried over MgSO4 and evaporated under vacuo to give the title compound (1.80 g) was obtained as a beige solid (95%) in 95.3% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [OH:1][C:2]1([CH3:8])[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>C(Cl)Cl>[C:16]([O:1][C:2]1([CH3:8])[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: CC1(O)CCSCC1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC1(C)CCSCC1
Temperature: 0 °C
Yield: 65.3 %

Procedure:
To a 200-mL three-necked flask fitted with a stirrer bar coated with Teflon™, were added 5.95 g of 4-hydroxy-4-methyltetrahydrothiopyran (manufactured by SANKYO KASEI Co., Ltd.), 5.08 g of triethyl amine, and 50 mL of dried methylene chloride, and the mixture was stirred under nitrogen atmosphere at 0° C. To the mixture, 5.0 g of methacryloyl chloride was slowly added through a dropping funnel, and the resulted mixture was reacted at 0° C. for 30 minutes, allowed to warm to room temperature, and was further reacted for another 5 hours. After confirming loss of the starting material by TLC, the reaction solution was poured in a 300-mL separatory funnel, washed with 100 mL of water followed by with 100 mL of saturated NaCl solution (brine), and dried with anhydrous sodium sulfate. From the obtained solution, the solvent was removed by an evaporator, to obtain an oily crude product. The crude product was purified by silica gel chromatography using a mixed solution of n-hexane and ethyl acetate to give 5.89 g of 4-methyl-tetrahydro-2H-thiopyran-4-yl methacrylate (thiopyran derivative of the following formula 3) (yield: 59.4%).
Reaction SMILES: [CH3:1][CH:2]([CH:6]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH2:3][C:4]#[N:5].ClCCl.ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[CH3:1][CH:2]([CH:6]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27]([CH3:28])=[O:40])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:14])[F:16])=[CH:9][CH:8]=1)[CH2:3][C:4]#[N:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C(C)CC#N)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: CC(CC#N)C(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
150 mg (0.37 mmol) of the compound from Example 54 were introduced into 20 ml of dichloromethane at 0° C., 92 mg (0.37 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 150 mg (96% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1)[O:7][CH2:6]2)=O.CO.Cl.[OH:25][NH2:26].C([O-])(=O)C.[Na+]>O>[OH:25][N:26]=[CH:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1)[O:7][CH2:6]2
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=O)ccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=NO)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 5′-formyl-3′H-spiro[azetidine-3,1-isobenzofuran]-1-carboxylate (Preparation 42, 1.5 g, 5.184 mmol, 1 eq) in mixture of methanol (20 mL) and water (10 mL) was added hydroxyl amine hydrochloride (0.537 g, 7.777 mmol, 1.5 eq) followed by addition of sodium acetate (0.765 g, 9.332 mmol, 1.8 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 24 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afforded yellow colored residue, which was diluted by water (70 mL) and extracted with ethyl acetate (3×30 mL). Combined organic phase was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get yellow semi solid (1.9 g, crude). Crude was purified by Combiflash using 40 g Redisep column. Desired compound was eluted in 24% ethyl acetate in hexane to afford title compound as yellow semi solid (1.1 g, 69.62%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.13 (d, J=9.6 Hz, 2H), 4.31 (d, J=9.84 Hz, 2H), 5.10 (s, 2H), 7.43 (s, 1H), 7.47 (d, J=7.88 Hz, 1H), 7.56 (d, J=7.92 Hz, 1H), 8.14 (s, 1H). (m/z): 303.3 (M−H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[CH:12][C:11]([C:14](OCC)=[O:15])=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:15][CH2:14][C:11]1[CH:10]=[N:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:13][CH:12]=1
Reactant: CCOC(=O)c1cnc(Nc2ccccc2)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OCc1cnc(Nc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
Ethyl 2-(phenylamino)pyrimidine-5-carboxylate (0.590 g, 2.42 mmol) obtained in Step 2 was dissolved in toluene (25 mL). After cooling to −78° C., a 1 mol/L diisobutyl aluminum hydride-toluene solution (7.30 mL, 7.30 mmol) was added to the solution, followed by stirring at −78° C. for 3 hours. The reaction mixture was added with ethyl acetate followed by stirring vigorously at room temperature. The mixture was sequentially washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain 5-hydroxymethyl-2-(phenylamino)pyrimidine (386 mg, 79%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.I[C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1>>[N:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Nc1ccc(I)cc1
Reactant: c1cn[nH]c1
Product: Nc1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (125° C., 24 hours), 1H-pyrazole (102 mg, 1.5 mmol) is coupled with 4-iodoaniline (220 mg, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 90 mg (57% isolated yield) of the desired product as an orange solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[NH:14][C:13](=[O:16])[NH:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:21]([NH:23][CH2:24][C:25](=[O:32])[N:26]1[CH2:30][CH2:29][C:28](=O)[CH2:27]1)=[O:22]>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:21]([NH:23][CH2:24][C:25](=[O:32])[N:26]1[CH2:27][CH2:28][CH:29]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[C:15]4[NH:14][C:13](=[O:16])[NH:12][C:11]=4[CH:10]=[CH:9][CH:8]=3)[CH2:5][CH2:6]2)[CH2:30]1)=[O:22]
Reactant: O=c1[nH]c2cccc(C3CCNCC3)c2[nH]1
Reactant: O=C1CCN(C(=O)CNC(=O)c2ccc(Cl)c(Cl)c2)C1
Product: O=C(NCC(=O)N1CCC(N2CCC(c3cccc4[nH]c(=O)[nH]c34)CC2)C1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 4-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one and 3,4-dichloro-N-(2-oxo-2-(3-oxopyrrolidin-1-yl)ethyl)benzamide using general procedure E. HPLC (Table 1, Method b) Rt 1.73 min; m/z: (M+H)+ 516.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CBr)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
Methyl 6-methyl nicotinate (1.05 g, 10 mmol) was dissolved in ethyl acetate (50 ml), followed by addition of NBS (3.56 g, 20 mmol) and AIBN (329 mg, 2 mmol). After stirring at 80° C. for 3 hours, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane; 4/1) to give the title compound (682 mg, 28%) as orange amorphous product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[CH:20]([O:19][CH:13]([CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH2:3][CH2:2][O:1][C:32]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:34])[F:35])=[CH:30][CH:29]=2)=[O:33])[CH:5]=1)[C:14]([OH:16])=[O:15])([CH3:21])[CH3:22]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:47])[NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]5[N:29]=[C:30]([C@@H:33]6[CH2:37][CH2:36][CH2:35][N:34]6[C:38](=[O:46])[CH2:39][C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=6)[NH:31][CH:32]=5)=[CH:24][CH:23]=4)[CH:17]=[CH:16][C:15]=3[S:48][C:49]3[CH:54]=[CH:53][C:52]([NH:55]C(=O)OC(C)(C)C)=[CH:51][CH:50]=3)=[N:11][CH:10]=[N:9][C:8]=2[N:63]=1)([CH3:3])[CH3:2].Cl.O1CCOCC1>O1CCCC1>[NH2:55][C:52]1[CH:51]=[CH:50][C:49]([S:48][C:15]2[CH:16]=[CH:17][C:18]([C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([C@@H:33]5[CH2:37][CH2:36][CH2:35][N:34]5[C:38](=[O:46])[CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[O:47])=[CH:19][C:14]=2[NH:13][C:12]2[C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:63][C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:54][CH:53]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)Cc6ccccc6)n5)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)Cc6ccccc6)n5)cc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Reaction time: 4 h
Yield: 41.9 %

Procedure:
To a solution of the Product of Example 1K (0.092 g, 0.11 mmol) in tetrahydrofuran (1 mL) was added 4 M HCl in dioxane (1 mL, 4.2 mol) at ambient temperature. After stirred for four hours, the solid HCl salt of the product was filtered off and taken up in a small amount of methanol and added to a NaHCO3 solution. The free amine was extracted into ethyl acetate, concentrated and purified by combi-flash 12 g column, eluting with 0-10% Methanol in dichloromethane to give a yellow solid (0.035 g, 43%). 1H NMR (400 MHz, Solvent) d ppm 1.36 (d, J=7.02 Hz, 6H) 1.89-2.36 (m, 4H) 3.24 (dd, J=13.89, 6.87 Hz, 1H) 3.50-3.81 (m, 4H) 5.09-5.20 (m, 1H) 6.66 (d, J=8.54 Hz, 2H) 6.98-7.10 (m, 2H) 7.12-7.35 (m, 7H) 7.55 (d, J=8.54 Hz, 1H) 7.66-7.79 (m, 5H) 7.96 (s, 1H) 8.49 (s, 1H) 8.76 (d, J=8.24 Hz, 1H)
Reaction SMILES: [CH:1]([C:3]12[CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][C:4]2([CH3:12])[C:10]#[N:11])=[O:2]>O1CCCC1.[Ru]>[OH:2][CH2:1][C:3]12[CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][C:4]2([CH3:12])[C:10]#[N:11]
Reactant: CC1(C#N)CC2CCC1(C=O)C2
Agent: [Ru]
Solvent: C1CCOC1
Product: CC1(C#N)CC2CCC1(CO)C2
Temperature: 90 °C
Reaction time: 12 h

Procedure:
416 g of (5 or 6)-formyl-2-methylbicyclo[2.2.1]heptane-2-carbonitrile (2.55 mol) was dissolved in 200 g THF (tetrahydrofuran), 20 g catalyst, 5% Ru on carbon (Aldrich), was added, and the whole reaction mixture was charged into a 1 L autoclave. The autoclave was heated to 90° C. and pressurized with 1000 psig H2 gas for 12 h while the progress of the reaction was periodically monitored by GC analysis. After venting the reactor, cooling to room temperature, and rinsing with THF, the reaction mixture was filtered though a plug of celite under nitrogen. Solvent was removed from the reaction mixture by rotary evaporation, and the residual oil (388 g) was distilled in vacuo to yield 275 g (1.66 mol) of (5 or 6)-(hydroxymethyl)-2-methylbicyclo[2.2.1]heptane-2-carbonitrile as colorless liquid (65% isolated yield). Boiling point: 93.3° C. at 80 mTorr. The product was pure by GC/MS analysis.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]#N)=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])[CH3:2].[OH-:31].[NH4+].[OH-:33].[Na+]>Cl>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:17]3[CH:24]=[CH:25][C:26]([C:28]([OH:33])=[O:31])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])[CH3:2]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C#N)ccc21
Reactant: [OH-]
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C(=O)O)ccc21
Yield: 83 %

Procedure:
A mixture of 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile (2.00 g, 5.0 mmol) and 6M HCl (50 mL) was heated to reflux for 12 h. After cooling, the final solution was neutralized by ammonium hydroxide and 1M NaOH to pH 6. The precipitate was collected by filtration and the solid washed with water thoroughly and dried in a vacuum oven to yield 1.74 g (83%) of 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5 carboxylic acid as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[N:10][CH:11]=1)=O)[CH3:2].B.C(O)(=O)C.Cl>O1CCCC1>[CH2:1]([N:3]([CH2:4][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[N:10][CH:11]=1)[CH2:15][CH3:16])[CH3:2]
Reactant: CCN(CC)C(=O)c1cnc2occc2c1
Agent: B
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(CC)Cc1cnc2occc2c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a solution of N,N-diethyl furo[2,3-b]pyridine-5-carboxamide (3.6 g, 16.5 mmol) in dry tetrahydrofuran (35 mL), under a nitrogen atmosphere, was added 1M borane in THF (52 mL, 52 mmol). This solution was warmed at 60° C. for 2-3 hours and then glacial acetic acid (3 mL, 52 mmol) was carefully added. After 0.5 hours, dilute hydrochloric acid (10%) was added to the reaction and the aqueous layer was separated and made basic with sodium hydroxide solution. The product was extracted into methylene chloride, dried over anhydrous sodium sulfate, filtered through a pad of charcoal and the solvent evaporated to give crude oily product (2.6 g). This material was distilled under vacuum to give purified produt (1.2 g, 36% yield), bp: 120°-121° C./1.5 mmHg. A small portion was treated with ethanolic hydrogen chloride to give the hydrochloride salt which was recrystallized from isopropanol, mp: 206°-208° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:12][CH2:11][CH2:10][CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCCc1ccccc1
Reactant: Cc1ccncc1C
Product: Cc1cnccc1CCCCc1ccccc1
Yield: 97 %

Procedure:
1.62 g (15.1 mmol) of 3,4-dimethylpyridine and 3.0 g (15.1 mmol) of 1-bromo-3-phenylpropane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 3.3 g of the desired compound (yield: 97.2%). The resulting compound was identified as 1-phenyl-4-(3-methyl-4-pyridyl)-butane (hereinafter referred to as compound 41) by the following analytical results.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[O:12][C:11](=[O:13])[NH:10][N:9]=1.[Cl:14][C:15]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18]>C(#N)C>[Cl:14][C:15]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:16]=1[C:17]([NH:19][C:20]([NH:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[O:12][C:11](=[O:13])[NH:10][N:9]=1)=[O:21])=[O:18]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: Nc1ccsc1-c1n[nH]c(=O)o1
Agent: Cl
Solvent: CC#N
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1ccsc1-c1n[nH]c(=O)o1
Reaction time: 3 h

Procedure:
5-(3-Aminothiophen-2-yl)-3H-[1,3,4]oxadiazol-2-one hydrochloride (30 mg) is initially charged in 3 ml of acetonitrile. The equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile is added. After 3 hours, the solid is filtered off with suction and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15](Cl)=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([Cl:13])[CH:10]=[N:9]1.[OH-].[Na+].[NH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([NH2:21])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([Cl:13])[CH:10]=[N:9]1
Reactant: CC(C(=O)Cl)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Reactant: N
Agent: [Na+]
Agent: [OH-]
Product: CC(C(N)=O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Reaction time: 0.5 h

Procedure:
3 g (10 mmoles) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionyl chloride are stirred into 30 ml of concentrated aqueous ammonia solution. Stirring is continued for a further half hour at room temperature; adjustment to pH 12 is effected with sodium hydroxide solution, followed by extraction with ether, drying of the ethereal phase and concentration. 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionamide (m.p. 131°-132° C.) is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:8][N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1
Reactant: O=Cc1ncc[nH]1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(Cc2ncc[nH]2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (21 mg, 0.061 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 2-imidazole carboxaldehyde (8.7 mg, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 20.3 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(1H-Imidazol-2-ylmethyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 11 as a colorless oil (10.7 mg, 54%). LRMS 327.
Reaction SMILES: C(O[BH-](O[C:11](=[O:13])[CH3:12])OC(=O)C)(=O)C.[Na+].[N+:15]([C:18]1[CH:19]=[C:20]2[C:26](=[CH:27][CH:28]=1)[CH:25]1O[CH:21]2[CH2:22][NH:23][CH2:24]1)([O-:17])=[O:16].C(=O)C.ClC(Cl)C>C(O)(=O)C>[CH2:22]([N:23]1[CH2:12][CH:11]2[O:13][CH:25]([C:26]3[C:20]2=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:28][CH:27]=3)[CH2:24]1)[CH3:21]
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CNCC2O1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN1CC2OC(C1)c1cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.6 %

Procedure:
Sodium triacetoxyborohydride (530 mg, 2.5 mmol) was added to a solution of 4-nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (200 mg, 0.97 mmol), acetaldehyde (0.15 mL, 2.5 mmol), acetic acid (0.1 mL) and dichloroethane (5 mL). The reaction was stirred at room temperature for 5 h. The reaction was then quenched with saturated aqueous NaHCO3 (10 mL), extracted with CH2Cl2 (2×10 mL), dried over MgSO4, filtered, and concentrated. The remaining residue was purified with silica gel chromatography (10-100% EtOAc in hexanes) to give 10-Ethyl-4-nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene as a yellow oil (115 mg, 51%). MS (m/e) 235 (M+1).