Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH:4]=[N:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[CH:8][CH:7]=1.[CH3:21][N:22]=[C:23]=[O:24]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.O1CCCC1>[CH3:21][NH:22][C:23](=[O:24])[O:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([N:5]=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[OH:1])=[CH:7][CH:8]=1
Reactant: CN=C=O
Reactant: Oc1ccccc1C=Nc1ccc(O)c2ccccc12
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc(N=Cc2ccccc2O)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a 350 milliliter glass pressure bottle equipped with a magnetic stirrer was added 4.00 grams (0.015 moles) of 4-(2-hydroxybenzylideneamino)-1-naphthol prepared in Part A, 1.03 grams (0.018 moles) of methyl isocyanate, 100 milliliters of tetrahydrofuran and 5 drops of dibutyl tin diacetate. The resulting reaction mixture was stirred for 18 hours at room temperature after which the volatiles were removed under reduced pressure and the remaining residue dissolved in ether. The ethereal solution was washed twice with a 1% aqueous sodium bicarbonate solution and twice with a saturated brine solution, dried over magnesium sulfate and concentrated under reduced pressure to give 4.87 grams (0.015 moles) of 4-(2-hydroxybenzylideneamino)naphth-1-yl methylcarbamate in the form of a pale yellow solid having a melting point of 143°-145.5° C. and the following structural formula: ##STR16##
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][C:10]1([CH3:19])[CH2:15][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]1=O>O.CO>[CH3:9][C:10]1([CH3:19])[CH2:15][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]1=[N:2][OH:3]
Reactant: CC1(C)CCCC(C)(C)C1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CCCC(C)(C)C1=NO
Temperature: 25 °C
Yield: 32.2 %

Procedure:
A solution of 2.3 g of hydroxylamine hydrochloride and 3.6 g of sodium acetate in 20 ml of water is added at RT to a solution of 3.4 g of 2,2,6,6-tetramethylcyclohexanone in 20 ml of MeOH and the reaction mixture is then refluxed for 48 hours. After cooling to RT, the precipitate formed is filtered off, washed with water and dried under vacuum to give 1.2 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH2:17]([O:24][CH2:25][C@H:26]([NH:30]C(OC(C)(C)C)=O)[C:27](O)=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[NH2:30][C@@H:26]([CH2:25][O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:27]([NH:12][C:11]1[CH:13]=[CH:14][C:8]([O:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: COc1ccc(Oc2ccc(N)cc2)cc1
Product: COc1ccc(Oc2ccc(NC(=O)[C@@H](N)COCc3ccccc3)cc2)cc1
Yield: 90 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-methoxyphenoxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(4-methoxyphenoxy)phenyl)propanamide (710 mg, 90%).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]1(=[O:16])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1>S(=O)(=O)(O)O>[N+:1]([C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][NH:7][C:6]2=[O:16])=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: O=C1NCCc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1NCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a cold solution consisting of potassium nitrate (8.2 g, 81.6 mmol) in sulfuric acid (40 mL) was added 1,2,3,4-tetrahydroisoquinolin-1-one (10 g, 68mmol) dropwise over a period of five minutes. The reaction mixture was stirred overnight at room temperature and then poured into ice. The solution was filtered. After washing with water several times, the solid was dried to yield the title compound (9.85 g, 76%).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[C:12]([O:16][C:17]([N:19]([CH3:30])[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[C:21]=1[CH3:29])=[O:18])([CH3:15])([CH3:14])[CH3:13]>O1CCCC1.O>[C:12]([O:16][C:17]([N:19]([CH3:30])[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([O:27][C:8](=[O:10])[CH3:9])=[C:22]([CH3:28])[C:21]=1[CH3:29])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: Cc1cc(N(C)C(=O)OC(C)(C)C)c(C)c(C)c1O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C)cc(N(C)C(=O)OC(C)(C)C)c(C)c1C
Reaction time: 1 h

Procedure:
5.64 ml of dehydrated triethylamine and 2.9 ml of acetyl chloride were added at room temperature to a solution of 7.2 g of N-t-butoxycarbonyl-N-methyl-4-hydroxy-2,3,5-trimethylaniline [prepared as described in step (f) above] in 100 ml of dehydrated tetrahydrofuran, and the resulting mixture was stirred for 1 hour, after which it was allowed to stand overnight. The reaction mixture was then diluted with water and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, after which the residue was triturated with ice-cooled hexane to cause crystallization. The crystals were collected by filtration and washed with ice-cooled hexane to give 6.25 g of the title compound, melting at 103-104° C.
Reaction SMILES: [C-]#N.[K+].Cl[CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:9].[OH2:17].[CH3:18][OH:19]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2([C:18]([OH:19])=[O:17])[CH2:7][CH2:6][CH2:5][O:9]2)=[CH:11][CH:12]=1
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Reactant: CO
Reactant: O
Agent: [C-]#N
Agent: [K+]
Product: O=C(O)C1(c2ccc(Cl)cc2)CCCO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Potassium cyanide (1.87 g, 28.78 mmol) was added to a solution of 4-chloro-4′-chloro-butyrophenone (5.00 g, 23.03 mmol) in 25 mL of methanol. After stirring for 3 days at room temperature, the reaction was poured into water (50 mL) and extracted with methylene chloride (3×50 mL). The organic layers were combined, washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (Biotage) over silica gel eluting with hexane/ethyl acetate (30:1) to give 3.52 g of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ 7.47 (m, 2H); 7.38 (m, 2H); 4.24 (m, 2H); 2.74 (m, 1H); 2.33 (m, 1H), 2.15 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:33]1(C)[C:37]2(CS(O)(=O)=O)[C:38](C[CH:34]1[CH2:35]C2)=[O:39].O1C=CCCC1>ClCCl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][CH:38]2[CH2:37][CH2:33][CH2:34][CH2:35][O:39]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: [O-][n+]1c(CCCCCCCCCCCO)cc(OCc2ccccc2)c2ccccc21
Agent: C1=COCCC1
Solvent: ClCCl
Product: [O-][n+]1c(CCCCCCCCCCCOC2CCCCO2)cc(OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
In this example, 5 m moles of 4-benzyloxy-2-(11-hydroxyundecyl)-quinoline-N-oxide is dissolved in dichloromethane, and a catalytic amount of D-camphorsulfonic acid and 6 m moles of 2,3-dihydropyran are added thereto. The mixture is stirred at room temperature for 3 hours. Then, the reaction solution is washed with an aqueous sodium hydrogen carbonate solution and then with water, and dried over anhydrous sodium sulfate. The solvent is removed therefrom by distillation, and the residue is purified by silica gel column procedure, whereby the cationed compound is obtained as a colorless oily substance (yield: 82.3%).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([OH:37])[CH:31]=1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([O:37][C:2]2[C:7](=[O:8])[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=2[CH2:27][CH3:28])[CH:31]=1
Reactant: Cc1cc(C)nc(O)c1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cc(C)cc(C)n2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 48.6 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.45 g), 4,6-dimethylpyridin-2-ol (0.19 g), 8 M potassium hydroxide solution (0.19 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.24 g, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:16](=[O:18])[CH3:17])=[C:4]([F:9])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(Br)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Br)cc1F
Reaction time: 0.17 h
Yield: 96.8 %

Procedure:
A solution of 4-bromo-2-fluorophenylamine (10.9 g, 57.4 mmol) and pyridine (9.4 mL, 115 mmol) in 50 mL of anhydrous dichloromethane was treated with acetyl chloride (3.33 mL, 63.1 mmol) at 0° C. After 10 minutes at 0° C. and 10 minutes at room temperature, the mixture was concentrated in vacuo and the residue was treated with 300 mL of 1 N aqueous sulfuric acid. The organic layer was concentrated in vacuo to give 12.9 g of N-(4-bromo-2-fluorophenyl)acetamide as a light greyish solid (97% yield).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH:9]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:11]=[CH:10]1>CC#N>[Cl:1][C:13]1[N:9]=[CH:10][NH:11][C:12]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1c[nH]cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)c1[nH]cnc1Cl
Reaction time: 12 h
Yield: 15.8 %

Procedure:
N-chlorosuccinimide (0.318 g, 2.4 mmol) was added to a stirred solution of methyl 1H-imidazole-4-carboxylate (0.300 g, 2.4 mmol) in CH3CN (16 mL). The reaction mixture was stirred for 12 h in the dark and then concentrated. The white residue was taken up in EtOAc, satd. aqueous Na2S (10 mL) was added and the solution was stirred for 15 min. The organic layer was isolated, dried (Na2SO4), concentrated and the crude product was purified by column chromatography (20-70% EtOAc/hexanes) to afford the title compound (0.061 g, 16%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (br. s., 1H), 7.85 (s, 1H), 3.81 (s, 3H). ES-LCMS: m/z 160.9, 162.9 (M+1).
Reaction SMILES: [CH:1]([Cl:4])(Cl)Cl.[C:5](Cl)(Cl)=[O:6].[CH3:9][N:10]1C[CH2:13][CH:12]([OH:15])[CH:11]1[CH3:16]>C(N(CC)CC)C>[Cl:4][CH2:1][CH2:13][CH:12]1[O:15][C:5](=[O:6])[N:10]([CH3:9])[CH:11]1[CH3:16]
Reactant: O=C(Cl)Cl
Reactant: CC1C(O)CCN1C
Reactant: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1C(CCCl)OC(=O)N1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a chloroform solution containing 68.12 g (0.7 mole) of phosgene at 0°-10° C. was added 80 g (0.7 mole) of 1,2-dimethyl-3-pyrrolidinol at a rate to maintain the temperature below 10° C. The reaction mixture was allowed to stir at room temperature overnight. The mixture was cooled in an ice bath and 100 ml of triethylamine was added dropwise maintaining the temperature below 10° C. The mixture was extracted in order with water, 3N hydrochloric acid solution, 3N sodium hydroxide solution and again with water. The chloroform layer was dried over anhydrous sodium sulfate and evaporated to yield 110 g of dark amber oil which was distilled at 113°-118° C. at 0.05 mm to give 80 g (64.8%) of pale yellow oil, n22 =1.4796.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6]C=C[C:3]=1[CH:8]1[O:12]CC[O:9]1.CS(C)=O.[CH2:17]([C:19]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:27]([O:37]C(=O)C)=[CH:26][C:20]=1[O:21][CH2:22][CH2:23][CH2:24]I)[CH3:18].P([O-])([O-])([O-])=O.[CH2:46]1[CH2:50][O:49][CH2:48][CH2:47]1>>[CH2:17]([C:19]1[CH:29]=[C:28]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[C:27]([OH:37])=[CH:26][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][O:49][C:48]1[CH:47]=[CH:46][CH:50]=[CH:6][C:7]=1/[CH:2]=[CH:3]/[C:8]([OH:12])=[O:9])[CH3:18]
Reactant: Oc1ccccc1C1OCCO1
Reactant: C1CCOC1
Reactant: CCc1cc(-c2ccc(F)cc2)c(OC(C)=O)cc1OCCCI
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1ccccc1/C=C/C(=O)O

Procedure:
60% Sodium hydride in oil was washed with hexane and suspended in dry DMSO (50 mL) with stirring under nitrogen. 2-(2-Hydroxyphenyl)-1,3-dioxolane (166 mg, 1 mmol) was dissolved in dry THF (10 mL) and added to the DMSO solution to give a pale yellow solution. After 20 minutes at room temperature 3-(2-ethyl-4-(4-fluorophenyl)-5-acetoxyphenoxy)propyl iodide (442 mg, 1 mmol) was added as a solution in dry THF (10 mL). After a further 2 hours at room temperature the reaction mixture was poured into pH 7.0 phosphate buffer and the mixture extracted 5 times with ether. The combined ether extracts were washed with water, dried with magnesium sulfate and evaporated to an oil which was chromatographed on a silica gel column eluting with ether/hexane (1:1). The title compound was isolated as an oil which was shown by the NMR spectrum to be contaminated with the starting phenol and a byproduct produced by loss of the acetyl group and alkylation produced with the starting iodide. These impurities could not be conveniently separated at this stage and the partially purified material was taken on to the next step.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:12])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][NH:11][C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCC(O)c1cccc(O)c1
Reactant: O=C1CCCCC1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: Oc1cccc(C2CNC3(CCCCC3)O2)c1

Procedure:
A suspension of 20 g. of 1-(3'-hydroxyphenyl)-2-amino-ethanol hydrochloride in 100 ml. of cyclohexanone is heated, while stirring vigorously, in a three-necked flask equipped with a dropping funnel, water separator, and thermometer. Above a temperature of 80°C., up to 100 ml. of benzene are added dropwise in such a manner so that the water of reaction formed together with the benzene is distilled of azeotropically. The temperature of the flask contents is, at the finish, about 130°C. After cooling, the crystalline reaction product is separated off, digested with benzene, and collected on a frit. There is obtained 20.3 g. (71.5% of theory) of 2-(3'-hydroxyphenyl)-1-oxa-4-azospiro[4,5]decane hydrochloride. After recrystallization from isopropanol/ethyl acetate, the product is obtained in the form of colorless crystals with a melting point of 138°-139°C.
Reaction SMILES: [CH:1]1([CH:7](O)[C:8]2[CH:9]=[C:10]([C:15]3(O)[CH2:20][CH2:19][S:18][CH2:17][CH2:16]3)[S:11][C:12]=2[CH2:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:25])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:25][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]1[CH:9]=[C:10]([C:15]2[CH2:20][CH2:19][S:18][CH2:17][CH:16]=2)[S:11][C:12]=1[CH2:13][CH3:14]
Reactant: CCc1sc(C2(O)CCSCC2)cc1C(O)C1CCCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1sc(C2=CCSCC2)cc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 4-{4-[cyclohexyl(hydroxy)methyl]-5-ethylthiophen-2-yl}tetrahydro-2H-thiopyran-4-ol (532 mg) synthesized in Example 85 (3) in toluene (10 mL) was added thionyl chloride (137 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (491 mg, 92%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4](N)=[N:5][O:6][C:7]=1[N:8]=[CH:9]OCC)#[N:2].[NH2:14][CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1.[CH2:24](O)C>>[CH3:24][C:4]1[C:3]2[C:7](=[N:8][CH:9]=[N:2][C:1]=2[NH:14][CH:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)[O:6][N:5]=1
Reactant: CCO
Reactant: NC1Cc2ccccc2C1
Reactant: CCOC=Nc1onc(N)c1C#N
Product: Cc1noc2ncnc(NC3Cc4ccccc4C3)c12

Procedure:
4-cyano-5-ethoxymethyleneamino-3-aminoisoxazole (320 mg, 1.8 mmol) (see J. Org. Chem., 29, 2116 (1964)) and 2-aminoindan (710 mg, 5.3 mmol) in dry ethanol (3 ml) were heated to reflux for 1.5 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=2:1). The product obtained was crystallized from ethanol to obtain the title compound (270 mg, 0.38 mmol) having the following physical properties:
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[N:36]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[C:1]([N:39]1[CH2:38][CH2:37][N:36]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40]1)(=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
To a solution of isobutyric acid (6.608 g, 75 mmol) in anhydrous dichloromethane (130 mL) was added triethylamine (8.33 g, 82.5 mmol), 1-hydroxybenzotriazole (10.125 g, 75 mmol), followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.25 g, 75 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C., and tert-butyl piperazine-1-carboxylate (13.97 g, 75 mmol) was added portion-wise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (200 mL), washed with saturated sodium bicarbonate (150 mL×2), 10% citric acid (150 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4-isobutyrylpiperazine-1-carboxylate (15 g, yield 78%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.13-1.14 (d, J=6.8 Hz, 6H), 1.47 (s, 9H), 2.75-2.82 (m, 1H), 3.43-3.58 (m, 4H); LC-MS (ESI) m/z: 257 (M+1)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:8](=[O:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.[C:33](OCC)(=[O:35])C.C([O-])(=O)C.[Na+]>CN(C)C=O>[CH3:6][N:7]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:8](=[O:24])[CH2:9][C:10]1[CH:11]=[C:12]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:14][C:15]=1[CH:33]=[O:35]
Reactant: CN(CCc1ccccc1)C(=O)Cc1cccc(OCc2ccccc2)c1
Reactant: CCOC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(CCc1ccccc1)C(=O)Cc1cc(OCc2ccccc2)ccc1C=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Phosphorus oxychloride (1.61 ml, 0.0173 mol) is added dropwise to 1.34 ml of N,N-dimethylformamide (DMF) while the reaction mixture is maintained between 10° to 20° C. with an external cooling bath. A solution of N-methyl-N-phenethyl-2-(3-benzyloxyphenyl)acetamide (3.73 g, 0.0144 mol) in DMF is added dropwise, the resulting mixture is heated at 100° C. for 6 hours. After cooling to room temperature, the reaction mixture is poured into an ice/H2O mixture, ethyl acetate is added, followed by 7.3 g of sodium acetate. The resulting mixture is stirred for 1 hour. The layers are separated. The organic layer is washed with 10 ml of 1N aqueous HCl and brine; dried (MgSO4) and concentrated concentrated in vacuo. The residue obtained is purified by a flash column packed with silica gel and eluted with 5% ethyl acetate in CH2Cl2 to give N-methyl-N-phenethyl-2-(5-benzyloxy-2-formylphenyl)acetamide. NMR confirms this structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.Cl[C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:13](=[O:14])[O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])[N:10]=2)[N:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cn2nc(Cl)ccc2n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1cn2nc(Cl)ccc2n1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine-2-amine (561 g, 3.3 mmol) in dimethylacetamide (11 ml) was added 2,2,2-trichloroethyl chloroformate (0.506 ml, 3.66 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction solution, and a solid was separated by filtration, which was washed with water to give 724 mg (63.3%) of the desired product as a solid.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.Cl.[CH3:9][N:10]([CH3:16])[C:11](=[O:15])[CH2:12][CH2:13][NH2:14]>C(O)C>[CH3:9][N:10]([CH3:16])[C:11](=[O:15])[CH2:12][CH2:13][NH:14][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: O=C1NC(=S)CS1
Reactant: CN(C)C(=O)CCN
Agent: Cl
Solvent: CCO
Product: CN(C)C(=O)CCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N,N-dimethyl-R-alaninamide (2.12 g) in ethanol (25 mL) was added 4-thioxo-1,3-thiazolidin-2-one (2.43 g), which N,N-dimethyl-β-alaninamide hydrochloride was treated with AMBERLYST (registered trademark) A21, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol) to give the title compound (0.33 g).
Reaction SMILES: O=[C:2]1[NH:17][C:5]2[CH2:6][C@H:7]3[C@H:12]([CH2:13][C:4]=2[O:3]1)[N:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9][CH2:8]3.P(Cl)(Cl)(Cl)(Cl)[Cl:19].P(Cl)(Cl)(Cl)=O.P(Br)(Br)[Br:30]>>[Cl:19][C:2]1[O:3][C:4]2[CH2:13][C@H:12]3[C@@H:7]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:14][CH2:15][CH3:16])[CH2:6][C:5]=2[N:17]=1.[Br:30][C:2]1[O:3][C:4]2[CH2:13][C@H:12]3[C@@H:7]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:14][CH2:15][CH3:16])[CH2:6][C:5]=2[N:17]=1
Reactant: BrP(Br)Br
Reactant: CCCN1CCC[C@H]2Cc3[nH]c(=O)oc3C[C@@H]21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN1CCC[C@H]2Cc3nc(Br)oc3C[C@@H]21
Product: CCCN1CCC[C@H]2Cc3nc(Cl)oc3C[C@@H]21

Procedure:
Trans-(±)-2-oxo-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1H-oxazolo[4,5-g]quinoline thus prepared can be reacted with phosphorous pentachloride or phosphorous oxychloride or PBr3 to yield the corresponding chloro or bromo derivative, trans-(±)-2-chloro-5-n-propyl-4,4a,5,6,7,8,8a,9-octa hydro-oxazolo[4,5-g]quinoline or trans-(±)-2-bromo-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-oxazolo[4,5-g]quinoline. This compound can in turn be reacted with secondary or primary amines with ammonia or with cyclic amines such as piperidine, pyrrolidine or morpholine to yield the corresponding 2-amino or substituted amino octahydro-oxazolo[4,5-g]quinoline.