Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:12][CH2:11][CH2:10][NH2:13])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: NCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCNCc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
p-Chlorobenzyl chloride, 32 g. (0.2 mole), was added dropwise to 60 g. (1.0 mole) of ethylenediamine heated at 80°. The solution was stirred at 80° overnight and then the excess amine was distilled in vacuo. The residue was triturated with i-PrOH to yield 32 g. of crude product. This material was dissolved in water, basified with dilute NaOH and the solution extracted with CH2Cl2. The combined extracts were dried (K2CO3) and concentrated in vacuo to an oil. The latter was distilled and the material boiling at 93°-95°/0.06 mm Hg was collected to yield 14.5 g. of the desired product, the identity of which was confirmed by examination of the NMR spectrum.
Reaction SMILES: [ClH:1].Cl.C1(C[N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)C=CC=CC=1.[H][H].C(O)C>CO.O.[Pd]>[ClH:1].[NH:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1
Reactant: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CO
Product: C1CC(N2CCOCC2)CCN1
Temperature: 60 °C

Procedure:
30.00 kg (90.01 mol) 4-[1-(phenylmethyl)-4-piperidinyl]-morpholine-dihydrochloride (M) were dissolved in 67.5 L methanol and 20.0 L water. Then the mixture was hydrogenated at a pressure of 4 bar and an internal temperature of 50° C. in the presence of 1.80 kg palladium on charcoal until no further uptake of hydrogen could be detected. After the reaction had ended the catalyst was filtered off and washed with a mixture of 18.0 L methanol and 2.0 L water. The hydrogenation solution obtained was then transferred into a reactor and heated to 60° C. At 60° C. 540.0 L ethanol were metered in. The resulting suspension was cooled to 5° C. The product was centrifuged off and dried.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f4) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13](Cl)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:16][NH:17][CH3:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13]([N:17]([CH3:18])[CH3:16])=[O:14])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Cl)N1CC(Sc2ccc(Cl)cc2)C1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC(Sc2ccc(Cl)cc2)C1
Reaction time: 3 h
Yield: 73.9 %

Procedure:
A solution of 2.6 g (0.01 mole) of 3-[(4-chlorophenyl) thio]-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was stirred while cooling in a water bath and treated with 2.5 ml (0.02 mole) of 40% dimethylamine in water. After stirring for 3 hr, the reaction mixture was diluted with 200 ml of water and the resulting product collected ny filtration (2.6 g). Recrystallization from acetone/isopropyl ether yielded 2 g (74.1%) of fine white crystals, m.p. 96°-97° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[O:18]=[C:19]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)CCC>[O:18]=[C:19]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:23][CH2:22]1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1cc(N2CCN(CC(=O)N3CCCC3)CC2)ncn1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.50 g, 3.86 mmol) and diisopropylethylamine (0.499 g, 3.86 mmol) were suspended in n-butanol and then 1-(2-oxo-2-pyrrolidin-1-ylethyl)piperazine 17-1 (0.762 g, 3.86 mmol) was added. The reaction was stirred at 150° C. for 18 hours and then the product was filtered off, washed with n-butanol and ethyl ether and air dried. 1H-NMR (CD3OD): 7.96 ppm (s, 1H); 5.72 ppm (s, 1H); 3.55 ppm (m, 6H); 3.44 ppm (t, 2H); 3.24 ppm (s, 2H); 2.60 ppm (t, 2H); 1.98 ppm (m, 2H); 1.88 ppm (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[C:22]([O:26][CH3:27])=[CH:21][C:19]=1[NH2:20]>>[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[C:22]([O:26][CH3:27])=[CH:21][C:19]=1[NH:20][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: COc1cc(N)c(Cl)cc1Cl
Product: COc1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)c(Cl)cc1Cl
Yield: 46.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2,4-di-chloro-5-methoxyaniline (125 mg, 0.65 mmol) to provide 201 (77 mg, 56% yield) as a white solid. LC-MS (M+H=386, obsd.=386).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CN1CCOCC1.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[C:22]([F:29])[CH:21]=1>ClCCl>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:25])=[C:22]([F:29])[CH:21]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(c1ccc(Br)cc1F)N1CCCC1CN1CCCC1

Procedure:
Procedure DD: To a stirring solution of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.0 mmol) and n-methylmorpholine (1.0 mmol) in dichloromethane (0.10M), slowly add 4-Bromo-2-fluorobenzoic acid chloride (1.0 mmol) diluted in dichloromethane. Stir reaction at room temperature for one hour. After this time wash the reaction with saturated aqueous sodium bicarbonate while extracting with dichloromethane. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo to give the title compound. MS (m/e): 355.1/357.1 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10](O)=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[CH2:10][OH:11]
Reactant: COc1ccccc1C(C)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1C(C)CO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96 %

Procedure:
As shown in step 4-ii of Scheme 4, to a solution of 2-(2-methoxyphenyl)propanoic acid (1.50 g, 7.91 mmol) in THF (20 mL) at 0° C. was added lithium aluminum hydride (31.6 mL of 0.5 M solution, 15.8 mmol) and the reaction was warmed to room temperature and stirred for 3.5 hours. After the sequential addition of 0.7 mL water, 0.7 mL 1M NaOH, 1.9 mL water, and MgSO4 to sequester the water, the reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give 2-(2-methoxyphenyl)-1-propanol as a clear, colorless liquid (Compound 2009, 1.41 g, 96% yield): 1H NMR (CDCl3) δ 7.27-7.20 (m, 2H), 7.03-6.87 (m, 2H), 3.85 (s, 3H), 3.67 (m, 2H), 3.54-3.42 (m, 1H), 1.54 (t, J=6.1 Hz, 1H), 1.29 (d, J=7.1 Hz, 3H).
Reaction SMILES: B(F)(F)F.CCOCC.[I:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=O)=[CH:13][CH:12]=1.[BH4-].[Na+]>C1COCC1>[I:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[CH:13][CH:12]=1
Reactant: O=C(Cc1ccc(I)cc1)N1CCOCC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Ic1ccc(CCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
BF3.Et2O (6.43 g, 45.3 mmol) was added to a solution of 2-(4-iodo-phenyl)-1-morpholin-4-yl-ethanone (3.0 g, 9.06 mmol) in THF (75 mL) at 0° C., stirred for 30 min, then NaBH4 (1.72 g, 45.3 mmol) was added at 0° C. The reaction mixture was slowly warmed to RT. After 16 h the reaction mixture was cooled to 0° C., quenched with ice-cold water, extracted with EtOAc (2×100 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The crude compound was purified by column chromatography using 100-200 mesh silica gel, eluted with 20-30% EtOAc in pet-ether to afford 1.56 g (Yield: 54.3%) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([F:22])=[CH:17][CH:18]=3)[NH:13][CH:12]2[C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([O:30][CH2:31][CH2:32][OH:33])=[C:25]([CH3:34])[CH:24]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([F:22])=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([O:30][CH2:31][CH2:32][OH:33])=[C:25]([CH3:34])[CH:24]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccc(N2C(=O)c3ccc(F)cc3NC2c2cc(C)c(OCCO)c(C)c2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3cc(F)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-(4-sec-butyl-phenyl)-7-fluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-2,3-dihydro-1H-quinazolin-4-one (0.11 g, 0.24 mmol) in anhydrous THF (30 mL) was added DDQ (0.09 g, 0.4 mmol) and the reaction mixture was stirred for 72 hours at room temperature. The solvent was evaporated in vacuo and the crude material was purified by column chromatography (silica gel; 230-400 mesh; 0.5% methanol/CH2Cl2 as eluent) to give the title compound (Q) as white solid. Yield: 0.06 g (50%). MP 53.9-54.4° C. 1H-NMR (400 MHz, CDCl3): δ 8.38 (dd, 1H), 7.43 (dd, 1H), 7.22-7.05 (m, 5H), 6.99 (s, 2H), 3.90 (m, 2H), 3.78 (m, 2H), 2.59 (m, 1H), 2.16 (s, 6H), 2.05 (t, 1H), 1.59 (m, 2H), 1.20 (d, 3H), 0.71 (t, 3H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][NH:29][C:30]([CH2:32][N:33]([CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:34])=[O:31]>>[CH3:28][NH:29][C:30]([CH2:32][N:33]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:40]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:41][CH:42]=1)[CH3:34])=[O:31]
Reactant: CNC(=O)CN(C)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: CNC(=O)CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-(methylcarbamoyl-methyl)-N-methyl-amino)-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C28H28N4O4
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC(C)COC)c3[nH]2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
A mixture of ethyl {2-[7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (580 mg), tetrahydrofuran (3 mL), ethanol (3 mL) and 1M aqueous sodium hydroxide solution (3 mL) was stirred at room temperature for 4 h. Water and 1M hydrochloric acid (3 mL) were added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound (510 mg, 93%) as a brown amorphous solid. MS 520 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH:7]([CH3:13])[C:8](OCC)=[O:9].[H-].C([Al+]CC(C)C)C(C)C.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH:7]([CH3:13])[CH2:8][OH:9]
Reactant: CCOC(=O)C(C)c1ncccn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CO)c1ncccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a solution of ethyl 2-(pyrimidin-2-yl)propanoate (1.7 g, 9.4 mmol) in THF (100 ml) at 0° C., was added diisobutylaluminium hydride (23.6 ml of a 1.0 M solution in THF, 23.6 mmol) dropwise. After 3 h NH4Cl (sat., 30 ml) was added and the mixture stirred at room temperature for 30 min. EtOAc (100 ml) was added and the mixture filtered. The filtrate was dried (Na2SO4) and evaporated. The residue was chromatographed on silica, eluting with CH2Cl2 :MeOH (95:5), to give the alcohol (562 mg, 43%) as a pale yellow oil. 1H NMR (360 MHz, CDCl3) δ 1.38 (3H, d, J=7.2 Hz), 3.22-3.31 (1H, m), 3.65 (1H, br s), 3.80-4.05 (2H, m), 7.18 (1H, t, J=4.9 Hz), 8.72 (2H, d, J=4.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:3]=1[C:4]([N:6]([CH2:11][C:12]1[N:13]=[N:14][C:15]([CH:21]([NH:23][CH:24]=O)[CH3:22])=[CH:16][C:17]=1[CH2:18][CH2:19][CH3:20])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5].O=P(Cl)(Cl)Cl>>[F:1][C:2]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:3]=1[C:4]([N:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:11][C:12]1[C:17]([CH2:18][CH2:19][CH3:20])=[CH:16][C:15]2[N:14]([CH:24]=[N:23][C:21]=2[CH3:22])[N:13]=1)=[O:5]
Reactant: CCCc1cc(C(C)NC=O)nnc1CN(CC(C)C)C(=O)c1cc(F)ccc1F
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1cc2c(C)ncn2nc1CN(CC(C)C)C(=O)c1cc(F)ccc1F
Temperature: 100 °C

Procedure:
A mixture of 2,5-difluoro-N-[6-(1-formylamino-ethyl)-4-propyl-pyridazin-3-ylmethyl]-N-isobutyl-benzamide (89 mg) and POCl3 (3 ml) is heated at 100° C. for 3 hours. The solvent is removed in vacuo and to the residue is added saturated NaHCO3 aqueous solution to neutralize the reaction mixture. EtOAc (10 ml) is added and the layers are separated. The aqueous layer is extracted with EtOAc (10 ml) and the combined extracts are washed with brine (10 ml), dried (Na2SO4) and evaporated. Flash column separation of the residue with 5% MeOH in CH2Cl2 gives the title compound as a light yellow oil. 1H NMR (CDCl3) (mixture of rotamers) 8.30 (s, 0.4H), 8.25 (s, 0.6H), 7.45 (s, 0.6H), 7.35 (s, 0.4H), 7.00-7.13 (m, 3H), 4.83 (s, 1.2H), 4.48 (s, 0.8H), 3.08 (d, 2H), 2.48 (s, 1.8H), 2.46 (s, 1.2H), 2.56 (t, 1.2H), 2.08-2.17 (m, 0.4H), 1.95-2.05 (m, 0.6H), 2.26 (t, 0.8H), 1.66-1.75 (m, 1.2H), 1.38-1.47 (m, 0.8H), 1.05 (t, 1.8H), 0.99 (d, 2.4H), 0.91 (t, 1.2H), 0.79 (d, 3.6H).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12]1)[CH2:7][CH2:8]C.[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>CCCCCC.O1CCCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([N:15]2[CH:11]([O:10][CH2:6][CH2:7][CH3:8])[CH2:12][CH2:13][C:14]2=[O:16])=[O:26])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCCCOC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCOC1CCC(=O)N1C(=O)c1ccc(OC)cc1
Reaction time: 2 h

Procedure:
11.2 cm3 of a 1.6M solution of n-butyllithium in n-hexane is added at -40° C. to a solution, cooled to -45° C., of 2.8 g of 5-n-butyloxy pyrrolidin-2-one in 70 cm3 of tetrahydrofuran with agitation for 30 minutes. Under the same conditions, a solution of 5.24 g of anisoyl chloride (at 58% in toluene) in 6 cm3 of tetrahydrofuran is added. After agitation for 2 hours, allowing to return to ambient temperature, the mixture is evaporated to dryness. The oil obtained is chromato-graphed on silica (eluent: toluene-ethyl acetate 8-2) and 2 g of the product sought is obtained.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[OH:7][N:8]=[C:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:10]([OH:12])=[O:11].CCOCC>C(Cl)Cl>[Cl:1][CH:2]([Cl:6])[C:3]([O:7][N:8]=[C:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:10]([OH:12])=[O:11])=[O:4]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=C(O)C(=NO)c1ccc(O)c([N+](=O)[O-])c1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)C(=NOC(=O)C(Cl)Cl)c1ccc(O)c([N+](=O)[O-])c1
Yield: 72.4 %

Procedure:
Dichloroacetyl chloride (14.7 g.) was dissolved in methylene chloride (50 ml.). To the solution was added 2-hydroxyimino-2-(3-nitro-4-hydroxyphenyl)acetic acid (5.65 g.) (syn isomer) with stirring under ice-cooling. The solution was stirred for 30 minutes at room temperature after ether (10 ml.) was added. To the reaction mixture was added petroleum ether under ice-cooling. The precipitates were collected by filtration and thorougly washed with petroleum ether to give 2-dichloroacetoxyimino-2-(3-nitro-4-hydroxyphenyl)-acetic acid (syn isomer) (6.1 g.), which was used as a starting material for the following acylating reaction without further purification.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[CH2:20]1>CCCCCC.CS(C)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[CH2:35]1[O:34][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]3[CH2:19][N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)=[CH:29][C:30]=2[O:36]1
Reactant: Cl[C@@H]1CCCCN(CCc2ccc3c(c2)OCO3)C1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: c1ccc2c(c1)COc1ccccc1N2C[C@H]1CCCCN1CCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (56 mg, 1.4 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (10 ml). The obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (250 mg, 1.27 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for 30 minutes. A solution of (R)-3-chloro-1-(3,4-methylenedioxyphenethyl)homopiperidine (426 mg, 1.40 mmol) in dimethyl sulfoxide (5 ml) was added dropwise into the obtained solution, and they were stirred at 50° C. for 2 hours. The reaction liquid was distributed in saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1) and then with hexane and ethyl acetate (4:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(3,4-methylenedioxyphenethyl)piperidine-2-ylmethyl] dibenzo [b,e][1,4] oxazepine in the form of a light yellow oil (171 mg, 30%).
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:27][C:28]2[N:29]=[CH:30][N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=2)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN([CH:44]=[O:45])C.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:27][C:28]2[N:29]=[C:30]([CH:44]=[O:45])[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=2)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)cn1)C1CCN(Cc2ccccc2)CC1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)c(C=O)n1)C1CCN(Cc2ccccc2)CC1
Yield: 61 %

Procedure:
A solution of n-butyllithium in hexane (1.5 M, 5.7 ml) was added dropwise a solution of tert-butyl (1-benzyl-4-piperidinyl)((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)carbamate (3.9 g) obtained in Example 83c) in THF (50 ml) at −40° C. under argon atmosphere. The reaction solution was mixed at −40° C. for 15 minutes, and then DMF (72 ml) was mixed, and mixed at room temperature for 15 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column (ethyl acetate:ethanol=10:1) to obtain the title compound as a pale yellow oil (2.5 g, 61%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8]O.Cl.[NH2:11][CH2:12][CH2:13][SH:14].C(O)(C)C.CO.[BrH:21]>>[BrH:21].[BrH:21].[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8][S:14][CH2:13][CH2:12][NH2:11]
Reactant: NCCS
Reactant: Cc1cn(C)c(CO)n1
Agent: Br
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Cc1cn(C)c(CSCCN)n1

Procedure:
The reaction of 1,4-dimethyl-2-hydroxymethylimidazole (2.5 g.) with cysteamine hydrochloride (2.5 g.) in aqueous hydrobromic acid by the method described in Example 1 (i) (a) gave 1,4-dimethyl-2-[(2-aminoethyl)thiomethyl]imidazole dihydrobromide (6.2 g.), m.p. 161°-163° (from isopropyl alcohol-methanol).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([OH:10])=O.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.Cl.[NH2:41][CH:42]1[CH:49]2[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:51][CH:43]1[CH2:44]3)[CH2:48]2>ClCCl.CN(C=O)C.O>[CH:43]12[CH2:51][CH:47]3[CH2:46][CH:45]([CH2:50][CH:49]([CH2:48]3)[CH:42]1[NH:41][C:8]([C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1])=[O:10])[CH2:44]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: Cn1ncc(C(=O)O)c1Cl
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reaction time: 1 h
Yield: 59.6 %

Procedure:
5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (64 mg, 0.4 mmol, CAS#: 54367-66-7, purchased from Oakwood) was dissolved in a mixture of dry dichloromethane (3.2 mL) and dry DMF (0.8 mL). DIPEA (0.28 mL, 1.6 mmol) and TSTU (145 mg, 0.44 mmol) were added to the above mixture. After the mixture was stirred for 1 h, the appearance of active ester was detected by LC-MS. Then 2-aminoadamantane hydrochloride (75 mg, 0.4 mmol) was added. After another 2 hours water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried under vacuum and purified by C-18 reversed phase HPLC with a gradient of 10-100% acetonitrile/water to give 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (70 mg, 60%). Mass spectrum: m/z: 294.1 (M+1).