Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].C(S([C:11]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:14]2=[N:15][CH:16]=[CH:17][C:18]([CH3:19])=[C:13]2[N:12]=1)(=O)=O)C>ClCCl>[CH3:1][O:2][C:11]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:14]2=[N:15][CH:16]=[CH:17][C:18]([CH3:19])=[C:13]2[N:12]=1
Reactant: CO
Reactant: CCS(=O)(=O)c1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
420 mg (2.2 mmol) of 28% methanol solution of sodium methoxide was added to 10 ml of a methanol solution of 0.44 g (0.96 mmol) of 2-ethylsulfonyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]- 3H-imidazo[4.5-b]-pyridine was dispersed in 150 ml of dichloromethane. The mixture was refluxed for 40 minutes. The solvent was distilled out at a reduced pressure. The residue was mixed with water and neutralized with 2N HCl. An extract with dichloromethane was washed with a saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled out at a reduced pressure. The residue was treated with ethanol and ether for recrystallization to obtain 300 mg of the above named compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CN(C=O)C.CCN(CC)CC.[CH2:33](Br)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(OCC)(=O)C.O>[CH2:33]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)[CH:6]=2)[CH2:1]1)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCNC3)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCN(CCc2ccccc2)C3)nc1
Yield: 37 %

Procedure:
Combine 6-(1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-nicotinamide (46.9 mg, 0.17 mmol), DMF (3 mL). Et3N (0.1 mL, 0.77 mmol), and phenethylbromide (52 uL, 0.38 mmol) in a 7 mL vial. Place the reaction vial on a shaker at 70° C. for 72 hours, and then add water and ethyl acetate. Wash the ethyl acetate layer several times with water, 10% LiCl, and dry over Na2SO4. Concentrate organic mixture and flash chromatograph using 30% THF, 4% 1.0 N NH3 in MeOH, 76% CH2Cl2 to afford 23.2 mg, (37% yield) of the title compound: MS m/z 374 (M+1).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]([CH3:41])([CH3:40])[CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:24][CH3:25])[N:13]=[C:12]([CH3:26])[C:11]=1[CH2:27][N:28]([CH3:39])[C@@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:24]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([CH2:22][CH3:23])[C:16]=1[C:14]1[N:13]=[C:12]([CH3:26])[C:11]([CH2:27][N:28]([CH3:39])[C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31][CH2:30]2)=[C:10]([CH2:9][CH2:8][C:7]([CH3:40])([OH:6])[CH3:41])[CH:15]=1)[CH3:25]
Reactant: CCc1cccc(CC)c1-c1cc(CCC(C)(C)O[Si](C)(C)C(C)(C)C)c(CN(C)[C@H]2CCCc3ccccc32)c(C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1-c1cc(CCC(C)(C)O)c(CN(C)[C@H]2CCCc3ccccc32)c(C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (S)-[4-[3-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-butyl]-6-(2,6-diethyl-phenyl)-2-methyl-pyridin-3-ylmethyl]-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (120 mg, 0.20 mmol) in THF (8 mL) is treated with tetrabutylammonium fluoride (1.6 mL of 1M solution in THF, 1.6 mmol) at 0° C. The mixture is stirred for 24 hours at room temperature. Aqueous work-up followed by purification by PTLC yields (S)-4-(6-(2,6-Diethyl-phenyl)-2-methyl-3-{[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amino]-methyl}-pyridin-4-yl)-2-methyl-butan-2-ol as a colorless oil. 1H NMR (CDCl3) 7.65-7.62 (m, 1H), 7.26 (dd, 1H), 7.18-7.06 (m, 5H), 6.96 (s, 1H), 4.02-3.97 (m, 1H), 3.88 (s, 2H), 2.99-2.93 (m, 2H), 2.84-2.2.72 (m, 2H), 2.74 (s, 3H), 2.53 (br s, 1H), 2.39-2.31 (m, 4H), 2.14-2.1.95 (m, 2H), 2.08 (s, 3H), 1.92-1.73 (m, 4H, 1.30 (s, 6H), 1.05 (t, 6H).
Reaction SMILES: [C:1](C1C=CC(OCC(O)=O)=CC=1)(C)(C)C.[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([NH2:26])[CH:20]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C[Si](OP(=O)=O)(C)C>[CH3:16][O:17][C:18]([C:19]1[CH:24]=[CH:23][C:22]2[NH:25][CH:1]=[N:26][C:21]=2[CH:20]=1)=[O:27]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Agent: C[Si](C)(C)OP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2[nH]cnc2c1
Temperature: 160 °C
Yield: 221.8 %

Procedure:
A mixture of (4-tert-butyl-phenoxy)acetic acid (300 mg, 1.4 mmol), 3,4-diaminobenzoic acid methyl ester (300 mg, 1.4 mmol) in PPSE (4.8 mL) was heated at 160° C. for 4 h. At the end of the reaction period, the mixture was taken to ethyl acetate and neutralized with aqueous sodium bicarbonate. The organic layer was separated and the aqueous solution extracted with ethyl acetate. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (EtOAc:Hexane=1:9˜4:6) to afford 2-2,4-tert-butyl-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester as a colorless powder (547 mg, 80% yield).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C1(N=C=NC2CCCCC2)CCCCC1.CCOCC>O1CCOCC1>[C:1]([O:9][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(ON1C(=O)CCC1=O)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Nicotinic acid (4.025 g, 0.0327 mol) and N-hydroxysuccinimide (3.763 g, 0.0327 mol) were dissolved in 130 ml of dioxane. Dicyclohexylcarbodiimide (6.75 g, 0.032 mol) in 20 ml of dioxane was added. The reaction mixture was then stirred at room temperature for 3 hours. The dicyclohexylurea which precipitated was removed by filtration and the solvent was removed by rotary evaporation. The crude product was recrystallized from ethyl acetate to give light yellow crystals which were then waashed with anhydrous ether. The product, obtained in 72% yield (5.2 g) and melting at 129°-131° C., has the formula: ##STR40##
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)[CH2:8][CH3:9].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.O>[CH2:7]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][OH:17])=[CH:20][CH:21]=1)[CH2:8][CH3:9]
Reactant: CCCOCc1ccc(C(=O)OC)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CCCOCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Into a suspension of lithium aluminum hydride (0.40 g) in diethyl ether (25 ml) was added dropwise at 0° C. a solution of methyl 4-(propoxymethyl)benzoate (2.09 g) in diethyl ether (25 ml) over a period of one hour. After stirring at room temperature for 2 hours, water (0.4 ml), a 15% aqueous solution of sodium hydroxide (0.4 ml) and water (0.4 ml) were added to the reaction mixture at 0° C., and the resulting mixture was stirred at room temperature for 2 hours. After addition of magnesium sulfate, the solid was removed by filtration. The filtrate was evaporated under reduced pressure to remove the solvent to obtain 4-(propoxymethyl)benzyl alcohol (1.81 g) as a colorless oily substance.
Reaction SMILES: C1(C2C3C(=CC=CC=3)C(=O)C2)C=CC=CC=1.II.BrCC(OCC)=O.[C:26]1([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1C=CC=CC=1.[Zn].[Pd].C(O)(=O)C.CCOCC.O>[C:26]1([CH:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:33]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)CC1C=C(c2ccccc2)c2ccccc21
Agent: [Pd]
Agent: CCOC(=O)CBr
Agent: II
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)CC1CC(c2ccccc2)c2ccccc21

Procedure:
3-Phenyl-1-indanone (83 g, 0.4 mol) was dried by refluxing in C6H6 (120 ml) with removal of the azeotroped H2O. To this solution was added Et2O (120 ml) and Zn wool (26.25 g, 0.4 mol). The reaction mixture was heated to near reflux and a crystal of I2 added. Ethyl bromoacetate (110 g, 0.6 mol) was added over 2 hours, the temperature being kept near reflux by heat of reaction and some external heating. After the addition, the mixture was stirred and refluxed for a further 0.5 hour, cooled and poured into ice and acetic acid. The mixture was extracted with Et2O. The Et2O was washed with 1% NH4OH, dried (Na2SO4), filtered and evaporated and the residue distilled to give a mixture of ethyl 3-phenylindene-1-acetate and its corresponding double bond isomer (83.6g) b.p. 145°-155° C. (0.1 mm). This mixture of esters was hydrogenated over 10% Pd/C (0.6g) to give ethyl 3-phenylindan-1-acetate. This ester was hydrolyzed by refluxing with sodium hydroxide in ethanol to give the title compound, m.p. 126°-9° C.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]1[CH:32]([CH3:38])[N:31]([C:39](=O)[CH3:40])[CH2:30][CH2:29][C:28]2=1>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]1[CH:32]([CH3:38])[N:31]([C:39](=[S:10])[CH3:40])[CH2:30][CH2:29][C:28]2=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(C(C)=O)C3C
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c3c(c2c1)CCN(C(C)=S)C3C
Yield: 40 %

Procedure:
Lawesson's reagent (520 mg) is added portionwise, at 110° C., to a solution of 1-(6-methoxy-1-methyl-2,3,4,9-tetrahydro- 1H-β-carbolin-2-yl)-1 -ethanone (500 mg) in anhydrous toluene (25 mL). After refluxing for 1 h and evaporation of the toluene, the product is chromatographed on silica gel (99/1 chlorofomvmethanol eluent) and the 1-(6-methoxy-1-methyl-2,3,4,9-tetrahydro- 1H-β-carbolin-2-yl)-1 -ethanethione is thus recovered (40% yield).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH3:30])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH3:30])[S:32]([CH3:31])(=[O:34])=[O:33])=[CH:26][CH:27]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNCc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
A mixture of the compound (100 mg) obtained in Example 4, methanesulfonyl chloride (30 mg), triethylamine (76 mg) and tetrahydrofuran (2 ml) was stirred at 0° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, and washed with water. The precipitate was collected by filtration to give the title compound (32 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:18][C:19]3[CH:25]=[C:24](I)[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([SH:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C.CO.C(Cl)Cl.[Cu]I>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:18][C:19]3[CH:25]=[C:24]([S:37][C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=[CH:29][CH:28]=4)[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1cccc2ccccc12
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc3ccc(I)cc3s2)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)N1CCN(c2nc3ccc(Sc4cccc5ccccc45)cc3s2)CC1
Temperature: 90 °C

Procedure:
A mixture of 4-(6-iodobenzothiazol-2-yl)piperazine-1-carboxylic acid benzyl ester (0.370 g, 0.77 mmol), 1-napthalenethiol (0.124 g, 0.77 mmol), CuI (0.015 g, 0.08 mmol), and K2CO3 (0.213 g, 0.77 mmol) in isopropanol was heated at 90° C. overnight, cooled to 25° C., diluted with 20% MeOH in CH2Cl2, and filtered through a pad of silica gel. The filtrate was concentrated in vacuo to provide the title compound which used in Example 41 without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([O:31][C:32]([O:34][CH3:35])=[O:33])=[CH:26][C:24]=1[NH2:25]>C(O)(C)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:25][C:24]3[CH:26]=[C:27]([O:31][C:32]([O:34][CH3:35])=[O:33])[C:28]([CH3:30])=[CH:29][C:23]=3[F:22])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Oc1cc(N)c(F)cc1C
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Solvent: CC(C)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c(F)cc1C
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of 7-benzyloxy4-chloro-6-methoxyquinazoline (800 mg, 2.6 mmol), (prepared as described for the starting material in Example 4 but with an aqueous work up), and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (570 mg, 2.89 mmol) in isopropanol (20 ml) was refluxed for 2 hours. After cooling to ambient temperature, the solid was filtered, washed with isopropanol and dried under vacuum to give 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy4-methylanilino)-6-methoxyquinazoline (1.0 g, 77%).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][C:9]2([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)[CH2:15][O:14][C:13]3=[CH:16][S:17][CH:18]=[C:12]3[O:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][C:9]2([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[CH2:15][O:14][C:13]3=[CH:16][S:17][CH:18]=[C:12]3[O:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CC2(Cc3ccc([N+](=O)[O-])cc3)COc3cscc3OC2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ccc(CC2(Cc3ccc(N)cc3)COc3cscc3OC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(See Scheme, FIG. 7). To a 200 mL round bottom flask was added 0.307 g (0.722 mmol) of 3,3-Bis(4-nitrobenzyl)-3,4-dihydro-2H-thieno[3,4-b][1,4]-dioxepine, 2.1 g (9.3 mmol) of tin(II) chloride dihydrate and 50 mL of ethyl acetate. The solution was heated to reflux for overnight. After heating, the mixture was allowed to cool to room temperature. After cooling, 20 mL of a 0.25 M solution of sodium carbonate and 100 mL of dichloromethane were added. This mixture was vigorously stirred for 30 minutes. The mixture was then filtered through a celite pad and poured into a 500 mL separatory funnel. The organic layer was removed and washed twice with 50 mL of water and once with 50 mL of brine. The solution was dried with MgSO4 and the solvent was removed in vacuo to give the product, 3,3-bis(4-aminobenzyl)-3,4-dihydro-2H-thieno[3,4-b][1,4]-dioxepine, in quantitative yield. IR, 1HNMR, 13CNMR in addition to TLC were used to confirm identity of the product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[C:21]([NH2:30])[CH:22]=[CH:23][C:24]=3[O:28][CH3:29])[CH2:19]2)=[O:17])=[O:8])[CH2:3][CH2:2]1.Cl.Cl[CH2:33][CH2:34][N:35]([CH2:37][CH2:38]Cl)[CH3:36].C(=O)([O-])O.[Na+].[OH-].[NH4+]>C(O)CCC>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[C:21]([N:30]4[CH2:38][CH2:37][N:35]([CH3:36])[CH2:34][CH2:33]4)[CH:22]=[CH:23][C:24]=3[O:28][CH3:29])[CH2:19]2)=[O:17])=[O:8])[CH2:3][CH2:2]1
Reactant: CN(CCCl)CCCl
Reactant: COc1ccc(N)c2c1CCC(C(=O)Nc1ccccc1C(=O)N1CCOCC1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CCCCO
Product: COc1ccc(N2CCN(C)CC2)c2c1CCC(C(=O)Nc1ccccc1C(=O)N1CCOCC1)C2
Temperature: 50 °C
Yield: 17.7 %

Procedure:
A solution of N-(morpholinocarbonylphenyl)-8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide (280 mg, 0.69 mmol), bis (2-chloroethyl)methyl amine hydrochloride (190 mg, 1.0 mmol) and sodium hydrogen carbonate (84 mg, 1.0 mmol) in n-butanol (20 mL) was heated at 90° C. for 5 h. After cooling, 2 M ammonium hydroxide (10 mL) was added and the mixture was heated at 50° C. for 1 h. The organic phase was evaporated in vacuo and the residue was purified by flash chromatography on a silica gel column using chloroform/ethanol/conc. ammonium hydroxide (90:10:0.5) as eluent to yield 60 mg (18%) of the title compound: EIMS (70 eV) m/z (relative intensity) 492 (50, M+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([OH:15])[CH3:14].[O-]CC.[Na+]>O>[CH2:13]([O:15][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=1)[CH3:14]
Reactant: CNC(=O)c1cnc(C)cc1Cl
Reactant: CCO
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1cc(C)ncc1C(=O)NC
Reaction time: 8 h

Procedure:
4-Chloro-6,N-dimethylnicotinamide (2.4 g) was dissolved with stirring in abs. ethanol (40 ml) and treated with sodium ethoxide (1.8 g). After stirring at RT for 4 h, the mixture was allowed to stand overnight. After addition of water, it was extracted 3 times with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 2.2 g of the desired compound were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[CH2:6][N:5]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[CH2:3]1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:11]=[C:4]2[CH2:3]1
Reactant: CN1Cc2cc(-c3ccccc3)cn2CC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCn2cc(-c3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
Borane-dimethyl sulfide complex (0.25 mL, 2.6 mmol) was added to cold tetrahydrofuran (6 mL) and stirred for 10 min. 2-Methyl-7-phenyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3-one (180 mg, 0.8 mmol) was added, and the reaction mixture allowed to warm to room temperature and stirred for 3 h. The mixture was poured slowly into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water then brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude compound. Purification by column chromatography over silica gel (100-200 mesh) using 8% ethyl acetate in petroleum ether afforded 2-methyl-7-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine (110 mg, 64%) as a solid.
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].S(O)(O)(=O)=O.Cl[C:27]1[NH:28][CH2:29][CH2:30][N:31]=1>CC(O)C>[CH:1]([NH:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:27]3[NH:31][CH2:30][CH2:29][N:28]=3)=[CH:18][CH:19]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: ClC1=NCCN1
Reactant: CC(C)NC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)NC(=O)N1CCC(Cc2ccc(NC3=NCCN3)cc2)CC1
Yield: 59.2 %

Procedure:
A mixture of 4-(1-isopropylaminocarbonylpiperidin-4-ylmethyl)-phenylamine (0.64 g, 2.31 mmol) and 2-chloro-2-imidazoline sulfate (0.70 g, 3.47 mmol) in 2-propanol (20 mL) was heated under reflux for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was diluted with water, basified with 10% sodium hydroxide solution and extracted into dichloromethane. The organic layer was washed with water and brine, dried (Na2SO4), and concentrated in vacuo. The crude product was chromatographed on neutral aluminum oxide, eluting with 5% methanol/dichloromethane, and crystallized from ethyl acetate containing some ethanol, to give 2-[4-(1-isopropylaminocarbonylpiperidin-4-ylmethyl)-phenyl]amino-imidazoline (0.47 g, 59%) as a white solid, m.p. 191-192° C.
Reaction SMILES: Cl.[NH2:2]O.[Cl:4][C:5]1[C:13]([CH:14]=O)=[C:12]([Cl:16])[C:11]([F:17])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]>C(O)=O>[C:14]([C:13]1[C:5]([Cl:4])=[C:6]([CH:10]=[C:11]([F:17])[C:12]=1[Cl:16])[C:7]([OH:9])=[O:8])#[N:2]
Reactant: NO
Reactant: O=Cc1c(Cl)c(F)cc(C(=O)O)c1Cl
Agent: Cl
Solvent: O=CO
Product: N#Cc1c(Cl)c(F)cc(C(=O)O)c1Cl
Temperature: 102.5 °C
Reaction time: 4 h

Procedure:
162 g of hydroxylamine hydrochloride were introduced into 2000 ml of formic acid (technical-grade, 85% strength). At 95° C., 950 g of 2,4-dichloro-5-fluoro-3-formylbenzoic acid (moistened with sulphuric acid, 42% strength) were introduced. As a result, the mixture foamed briefly and then a clear solution was immediately obtained. The mixture was then stirred for 4 hours at from 100 to 105° C. (reflux).
Reaction SMILES: [N:1]([CH:4]([CH2:13][CH3:14])[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7])=[N+:2]=[N-:3]>FC(F)(F)C(O)=O>[N:1]([CH:4]([CH2:13][CH3:14])[CH2:5][C:6]([OH:8])=[O:7])=[N+:2]=[N-:3]
Reactant: CCC(CC(=O)OC(C)(C)C)N=[N+]=[N-]
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC(=O)O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butyl 3-azidopentanoate (1.84 g, 9.23 mmol) was dissolved in 99% trifluroacetic acid (2 ml) and stirred at room temperature for 1 h and evaporated to dryness. The traces of solvent and isobutylene were removed in vacuo to give an oily substance (990 mg, 44.0%). ir (neat) νmax : 3100 (broad, OH), 2100 (N3) and 1710 cm-1 (C=O of acid); 1Hmr (CDCl3) δ: 1.06 (3H, t), 1.60 (2H, q), 2.57 (2H, d), 3.43 (H, m) and 11.73 ppm (H, s). Anal. calcd for C5H9N3O2 : C 41.95, H 6.33; found: C 41.22, H 6.05.
Reaction SMILES: [C:1](OC)(=O)[C:2]([CH3:4])=O.[CH3:8][O:9][C:10](=[O:24])[C@H:11]([CH3:23])[NH:12][C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][CH2:21][O:22][C:15]=2[CH:14]=1>C(O)C(C)C>[CH2:8]([O:9][C:10](=[O:24])[C@H:11]([CH3:23])[NH:12][C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][CH2:21][O:22][C:15]=2[CH:14]=1)[CH:2]([CH3:4])[CH3:1]
Reactant: COC(=O)C(C)=O
Reactant: COC(=O)[C@H](C)Nc1ccc2c(c1)OCCO2
Solvent: CC(C)CO
Product: CC(C)COC(=O)[C@H](C)Nc1ccc2c(c1)OCCO2

Procedure:
Following reductive amination General Procedure AA above and using 1,4-benzodioxa-6-amine (Aldrich) and methyl pyruvate (Aldrich), N-(3,4-ethylenedioxyphenyl)alanine methyl ester was prepared. The methyl ester was then transesterified following General Procedure AQ above using iso-butanol to provide the title compound. Purification was by preparative plate chromatography.