Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[C:13]([CH3:14])=[C:12]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:17])[O:11][N:10]=1.Cl[C:25]1[S:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[N:26]=1.C(N(CC)CC)C.CN(C)C=O>O>[CH3:8][C:9]1[C:13]([CH3:14])=[C:12]([NH:15][C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:25]3[S:29][N:28]=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])[N:26]=3)[CH2:22][CH2:23]2)=[O:17])[O:11][N:10]=1
Reactant: Fc1ccccc1-c1nsc(Cl)n1
Reactant: Cc1noc(NC(=O)N2CCNCC2)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccccc4F)ns3)CC2)c1C
Yield: 15.5 %

Procedure:
A solution of N-(3,4-dimethylisoxazol-5-yl)piperazine-1-carboxamide trifluoroacetate (297 mg, 0.707 mmol), 5-chloro-3-(2-fluorophenyl)-1,2,4-thiadiazole (152 mg, 0.707 mmol), triethylamine (0.491 ml, 3.53 mmol) and N,N-dimethylformamide (3 ml) was stirred at room temperature for 0.5 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to obtain the desired product (44.0 mg, 15.5%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[C:21]([O:23][CH3:24])=[O:22])[NH:6][CH:7]=[C:8]1[C:13](=[O:14])OC(C)(C)OC1=O.C(=O)=O>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:18]([C:13](=[O:14])[CH:8]=[CH:7][NH:6]2)=[CH:19][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OC
Agent: O=C=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COC(=O)c1cc2c(=O)cc[nH]c2cc1OC
Temperature: 185 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
5-((3-Methoxy-4-methoxycarbonylanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g, 29.8 mmol) was suspended in DOWTHERM A, (trade mark of Fluka Chemie AG), (125 ml) and heated to 180-190° C. over 30 minutes. The starting material dissolved at 100° C. and carbon dioxide came off at approximately 180° C. The heating was stopped after a further 30 minutes and the product precipitated out as the temperature dropped. Upon reaching 40° C. ether was added and the mixture was stirred for 30 minutes. The solid was collected by filtration, washed with ether and dried under vacuum to give 7-methoxy-6-methoxycarbonyl-1,4-dihydroquinolin-4-one (5.56 g, 80%).
Reaction SMILES: N#N.[Br:3][C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>ClCCl>[Br:3][C:4]1[CH:12]=[CH:11][C:7]2[N:8]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[N:9]=[N:10][C:6]=2[CH:5]=1
Reactant: Brc1ccc2[nH]nnc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: N#N
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1ccc2c(c1)nnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 250-mL round-bottom flask equipped with a magnetic stir bar, a rubber septum and N2 inlet was charged with 5-bromo-1H-benzo[d][1,2,3]triazole (4.5 g, 22.7 mmol) and anhydrous dichloromethane (114 mL). To this solution, 3,4-dihydro-2H-pyran (10.3 mL, 113.6 mmol) was added in one portion at room temperature followed by addition of PPTS (0.57 g, 2.27 mmol). The resulting mixture was stirred at room temperature for 48 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with water and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with saturated NaHCO3 (50 mL), water (100 mL), and then brine (50 mL), dried over sodium sulfate, filtered and concentrated to give the crude product that was purified on a silica gel column eluted with 0-10% ethyl acetate in hexanes affording the title compound as a clear oil (3.6 g). LCMS: 198 [(M-THP+H)+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH:6]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)=[O:4].[C:19]1([C:25]2[N:26]=[C:27]([CH2:36]Br)[O:28][C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:17])([F:18])[C:3]([N:5]([CH:6]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH2:36][C:27]1[O:28][C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:26]=1)=[O:4]
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: COc1cccc2c1CCC2NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CCC2N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)C(=O)C(F)(F)F
Reaction time: 12 h
Yield: 35.9 %

Procedure:
To a solution of 1-trifluoroacetamido-2,3-dihydro-4-methoxy-1H-indene (0.44 g) and 4,5-diphenyl-2-bromomethyloxazole (0.55 g) in DMF was added K2CO3 (0.30 g). After being stirred for 12 hours, the solution was extracted with ethyl acetate. The mixture was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-[N-trifluoroacetyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.30 g). MS (m/z): 493 (M+ +1) IR (Nujol): 1680 cm-1NMR (CDCl3, δ): 2.15-2.45 (1H, m), 2.78-3.20 (2H, m), 2.50-2.75 (1H, m), 3.82 (3H, s), 4.38 (1H, d, J=16.2 Hz), 4.62 (1H, d, J=16.2 Hz), 5.77 (1H, t, J=7.5 Hz), 6.73 (1H, d, J=8.1 Hz), 6.76 (1H, d, J=7.5 Hz), 7.16 (1H, dd, J=7.5, 8.1 Hz), 7.32-7.34 (6H, m), 7.48-7.59 (4H, m)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C([S:13]P([O-])(OCC)=S)C.Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]([NH2:6])=[S:13]
Reactant: CCOP([O-])(=S)SCC
Reactant: COc1ccccc1C#N
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccccc1C(N)=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.5 g of o-methyoxybenzonitrile and 8.22 ml of diethyldithiophosphate in 200 ml of ethyl aceate was saturated with hydrogen chloride gas, and the resulting reaction mixture allowed to stir overnight at room temperature. The solvent was removed in vacuo and the oily residue triturated with hexane. The resulting solid was filtered and dried, 3.6 g.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O[C@H]1CCNC1
Product: O[C@H]1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Yield: 17 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (S)-3-pyrrolidinol to give the title compound in 17% yield; NMR Spectrum: 1.50-1.54 (m, 1H), 1.91-1.96 (m, 1H), 2.40 (dd, 1H), 2.55 (dd, 1H), 2.66 (dd, 1H), 2.80-2.89 (m, 3H), 4.16 (br s, 1H), 4.40 (t, 2H), 4.69 (br s, 1H), 5.28 (s, 2H), 7.24 (d, 1H), 7.37 (t, 1H), 7.55-7.58 (m, 2H), 7.87 (t, 1H), 7.92 (d, 1H), 8.29 (s, 1H), 8.45 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 482 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH:30]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[Li+].[OH-].O>C1COCC1.O.CO>[OH:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([N:10]([C:11]([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:27]3[CH2:32][CH2:31][CH:30]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:29][CH:28]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:21][CH2:22]1
Reactant: COC(=O)c1sc(C2=CCC(Oc3ccccc3)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCC(Oc4ccccc4)CC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4-phenoxy-cyclohex-1-enyl)-thiophene-2-carboxylic acid methyl ester (30 mg, 0.05 mmol) in THF: H2O: MeOH (3:1:2) (2 mL), was added LiOH in water (1N) (0.2 mL, 0.2 mmol). The reaction mixture was stirred at 70° C. for 4 h. The reaction mixture was concentrated under reduced pressure on a rotary evaporator. The mixture was partitioned between ethyl acetate and water. The water layer was acidified using 0.1 N HCl. The EtOAc layer was separated and dried over Na2SO4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by HPLC purification afforded 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4-phenoxy-cyclohex-1-enyl)-thiophene-2-carboxylic acid (3 mg, 10%) as a foam.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH:5]=[CH2:6].Br.Br.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[CH:5]([O:4][CH2:3][CH2:2][N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:18]2[N:17]([CH2:16][C:13]3[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=2)[CH2:28][CH2:29]1)=[CH2:6]
Reactant: C=COCCCl
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C=COCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 32 %

Procedure:
A mixture of 1.6 parts of 1-chloro-2-(ethenyloxy)ethane, 7.3 parts of 1-(4-fluorophenylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 3.1 parts of sodium carbonate, 0.1 parts of potassium iodide and 135 parts of N,N-dimethylformamide was stirred and heated overnight at 70° C. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1.9 parts (32%) of N-[1-[2-(ethenyloxy)ethyl]-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine; mp. 138.5° C. (compound 1).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=2[O:7][CH2:6][C:5]1=[O:20].[C:21]1([C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([SH:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:30]1([C:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([S:29][CH2:2][CH2:3][N:4]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=3[O:7][CH2:6][C:5]2=[O:20])[CH3:28])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(S)(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1cccc2c1OCC(=O)N2CCO
Product: COC(=O)COc1cccc2c1OCC(=O)N2CCSC(C)(c1ccccc1)c1ccccc1
Yield: 42 %

Procedure:
The same process as Example 1 was repeated except that methyl (4-(2-hydroxyethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate (187 mg) and 1,1-diphenylethanethiol (270 ml) were used to obtain the object compound (172.5 mg, yield 42%).
Reaction SMILES: [F:1][C:2]1([F:42])[CH2:3][CH2:4][N:5]([C:28]([C:30]2[S:34][C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:32][C:31]=2[CH3:41])=[O:29])[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18](N(OC)C)=[O:19])[CH2:14][CH2:13]1)=[O:11].[CH3:43][Li].Cl>O1CCCC1.C(OCC)C>[F:1][C:2]1([F:42])[CH2:3][CH2:4][N:5]([C:28]([C:30]2[S:34][C:33]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[N:32][C:31]=2[CH3:41])=[O:29])[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:13][CH2:14][CH:15]([C:18](=[O:19])[CH3:43])[CH2:16][CH2:17]1)=[O:11]
Reactant: CON(C)C(=O)C1CCN(C(=O)/C=C2/c3ccccc3N(C(=O)c3sc(-c4ccccc4)nc3C)CCC2(F)F)CC1
Reactant: [Li]C
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)C1CCN(C(=O)/C=C2/c3ccccc3N(C(=O)c3sc(-c4ccccc4)nc3C)CCC2(F)F)CC1
Temperature: -30 °C
Reaction time: 3 h

Procedure:
To a solution of 140 mg of (Z)-(1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}-4-piperidyl)-N-methoxy-N-methylcarboxamide in 10 ml of tetrahydrofuran was added 280 μl of a solution of 1.05N methyl lithium in diethyl ether at −30° C. This was stirred at −30° C. for three hours together while adding 200 μl of the above-mentioned methyl lithium solution thereto every 40 minutes. To the reaction solution was added 1N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate, followed by evaporating the solvent therefrom. The residue was purified by silica gel column chromatography (eluting with chloroform) to give 20 mg of (Z)-4,4-difluoro-5-[2-(4-acetylpiperidino)-2-oxoethylidene]-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepine as a yellow amorphous solid.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][C:7]1[N:12]=[C:11]([C:13]2[N:14]=[C:15]([N:18]=[C:19]([NH2:21])[NH2:20])[S:16][CH:17]=2)[CH:10]=[CH:9][CH:8]=1.[O-:22][C:23]#[N:24].[K+].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:20][C:19](=[N:18][C:15]1[S:16][CH:17]=[C:13]([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][CH2:5][NH:4][C:23]([NH2:24])=[O:22])[N:12]=2)[N:14]=1)[NH2:21]
Reactant: NCCc1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: N#C[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC(=O)NCCc1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.6 %

Procedure:
A mixture of 4-[6-(2-aminoethyl)pyridin-2-yl]-2-(diaminomethyleneamino)thiazole trihydrochloride (1.5 g) and potassium cyanate (0.5 g) in water (30 ml) was stirred for 5 hours at ambient temperature. The reaction mixture was adjusted to pH 9.5 with potassium carbonate and the mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 2-(diaminomethyleneamino)-4-[6-(2-ureidoethyl)pyridin-2-yl]thiazole (0.55 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][N:18](C)[C:19](=O)OCC2C=CC=CC=2)[CH2:13][CH2:12]1>C(O)C.[Pd]>[CH3:19][NH:18][CH2:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([C:3]2[N:2]([CH3:1])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=2)[CH2:12][CH2:13]1
Reactant: CN(C[C@H]1CC[C@H](c2nc3ccccc3n2C)CC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CNC[C@H]1CC[C@H](c2nc3ccccc3n2C)CC1

Procedure:
5.9 g of benzyl [[trans-4-(1-methyl-2-benzimidazolyl)cyclohexyl]methyl]methylcarbamate are dissolved in 600 ml of ethanol and hydrogenated at room temperature and normal pressure after the addition of 1 g of 5% palladium-on-active charcoal. The product. isolated in the usual manner, is chromatographed on 250 g of silica gel firstly with methylene chloride/methanol (1:1) and then with methanol/concentrated ammonium hydroxide (100:1) as the elution agent. There are obtained 3.3 g (85%) of 2-[trans-4-[(methylamino)methyl]cyclohexyl]-1-methyl-benzimidazole as a thick oil.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=[O:6])[CH3:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CC.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[CH3:5][C:4](=[O:6])[CH2:3][CH2:2][CH2:1][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCC(C)=O
Temperature: 90 °C
Yield: 95 %

Procedure:
To a 2 L two-necked round bottom flask equipped with water condenser, calcium chloride guard tube and mechanical stirrer, 70 g of 2,4-pentanedione, 650 g of 1-bromooctadecane, 8 g of 18-crown-6, anhydrous potassium carbonate 140 g and 600 ml of absolute ethanol were added with stirring. The mixture was refluxed at 90° C. with continuous stirring for 30 hrs; after refluxing at the said temperature, the mixture cooled to ambient temperature (25° C.), 600 ml of water was added to it and the 2-heneicosanone was extracted with dichloromethane from the mixture. On distillation of dichloromethane, 2-heneicosanone was obtained.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15](=[O:26])[C:16]([C:19]4[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=4)=[N:17]O)=[CH:14][C:9]=3[N:8]([CH3:27])[C:7]2=[O:28])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:29].[H][H]>C(O)C.C(OCC)C.[Pd]>[ClH:29].[NH2:17][CH:16]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[CH:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:7](=[O:28])[N:8]([CH3:27])[C:9]=2[CH:14]=1)[OH:26]
Reactant: [H][H]
Reactant: Cc1cccc(C(=NO)C(=O)c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Cc1cccc(C(N)C(O)c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)c1
Reaction time: 3 h
Yield: 92.4 %

Procedure:
1-(1-Cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-2-m-tolyl-ethane-1,2-dione 2-oxime (5 gm, 13.2 mmol) was dissolved in ethanol (300 mL) in a Parr bottle. Concentrated HCl (3.3 mL, 40 mmol) was added, followed by 10% Pd on carbon (approximately 0.5 gm). The resulting mixture was placed on a Parr hydrogenation apparatus and hydrogenated at a hydrogen pressure of 40 psi. Hydrogen consumption slowed considerably after 3 hours, with the amino ketone being formed initially. Hydrogenation was continued overnight, after which time the reaction was determined to be complete. The mixture was filtered through a celite plug and the filtrate was concentrated in vacuo to afford a viscous yellow oil, which was triturated/repulped in diethyl ether to afford 4.90 gm of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([N+:21]([O-])=O)[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Zn]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([NH2:21])[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCSc1noc2c([N+](=O)[O-])cccc12
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCSc1noc2c(N)cccc12
Yield: 100.9 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethylthio)-7-nitro-1,2-benzisoxazole (250 mg) in 90% aqueous acetic acid (2 ml) was added zinc powder (250 mg) with stirring under ice cooling, and the mixture was then stirred at room temperature for 30 minutes. After the completion of the reaction, the reaction mixture was filtered with Celite and the filtrate was concentrated under reduced pressure. Water was added to the residue, then extracted with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous magnesium sulphate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silical gel column chromatography with ethyl acetate as an eluent, to give the title compound (230 mg, quant).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13]4)[CH3:2].Cl.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH2:29][CH:28]=[CH2:27])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13]4)[CH3:2]
Reactant: C=CCBr
Reactant: CCc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(CC)cc13
Reaction time: 2 h

Procedure:
To a stirred solution of 3-Ethylmorphinan.HCl 46 (3 mg, 0.01 mmol) in dry DMF (0.6 mL) was added potassium carbonate (5 mg, 0.036 mmol), allyl bromide (5.0 μL, 0.060 mmol) sequentially and the mixture was refluxed. After 2 h, the mixture was dried over anhydrous MgSO4, filtered, and concentrated. Column chromatography of the product gave -2 mg of white solid. 1H NMR (300 MHz, CDCl3) δ 6.89˜7.16 (3H, m); 5.80 (1H, d); 5.16˜5.30 (2H, m); 4.00˜4.30 (1H, dd); 3.68 (2H, t); 3.66 (1H, m); 3.15 (1H, br); 2.68 (2H, m); 2.50 (2H, m); 2.38 (1H, m); 1.10˜1.70 (13H, m).
Reaction SMILES: [CH2:1]([C:4]([NH2:10])([CH2:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH2:2][CH3:3].Br[CH2:12][CH:13]=[O:14].[OH-].[Na+]>CO>[CH2:1]([C:4]([NH:10][CH2:12][CH:13]=[O:14])([CH2:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH2:2][CH3:3]
Reactant: C#CC(N)(CCC)CCC
Reactant: O=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CC(CCC)(CCC)NCC=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1,1-Dipropylprop-2-ynylamine (1.6 mole), the diethyl acetal of 2-bromoacetaldehyde (1.0 mole) and methanol (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 6 hours. After this time the reaction mixture is cooled to room temperature and sodium hydroxide (20 grams) is added. The reaction mixture is then stirred for an additional period of about 16 hours. The mixture is then filtered and the filtrate is distilled to yield the desired product the diethyl acetal of 2-(1,1-dipropylprop-2-ynylamino)acetaldehyde.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]O.[OH-].[Na+].Cl>CO.O>[C:1]1([CH:7]2[O:25][CH:8]2[C:9]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: O=C1NC(=O)C(Cc2ccc(C(=O)/C=C/c3ccccc3)cc2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(C(=O)C3OC3c3ccccc3)cc2)S1
Yield: 79.2 %

Procedure:
To a solution of title product of Example 39 (0.5 g, 1.5 mmol) in methanol (4 ml), cooled to 0° C., was added 30% H2O2 (0.5 ml, 4.8 mmol), followed by 2N NaOH (1.6 ml, 3.2 mmol). After 30 minutes at 0° C. the solution was acidified with 2N HCl, diluted with water (15 ml) and extracted with ethyl acetate (2×15 ml). The combined extracts were washed with brine (15 ml), dried over magnesium sulfate and concentrated in vacuo, leaving present title product as an oil (420 mg, 80%).