Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][C:6]([NH:8][CH:9]([CH2:16]O)[CH2:10][C:11]1[S:15][CH:14]=[N:13][CH:12]=1)=[S:7])(C)(C)C.[ClH:18]>>[ClH:18].[ClH:18].[S:15]1[C:11]([CH2:10][CH:9]2[CH2:16][S:7][C:6]([NH2:5])=[N:8]2)=[CH:12][N:13]=[CH:14]1
Reactant: CC(C)(C)NC(=S)NC(CO)Cc1cncs1
Agent: Cl
Product: NC1=NC(Cc2cncs2)CS1
Temperature: 110 °C

Procedure:
a solution of 0.56 g of N-(tert-butyl)-N′-[(1RS)-1-hydroxymethyl-2-(5-thiazolyl)ethyl]thiourea in 5.5 cm3 of 6N hydrochloric acid is heated at a temperature in the region of 110° C. for 3 hours. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 60° C., taken up in 4 cm3 of ethanol and 6 cm3 of diethyl ether and evaporated under the same conditions as above. The residue is taken up in 6 cm3 of ethanol and filtered, and the solid is dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40° C. and then dissolved in 5.5 cm3 of 6N hydrochloric acid solution and refluxed at a temperature in the region of 110° C. for 9 hours. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. and dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40° C., to give 0.54 g of (4RS)-4-(5-thiazolylmethyl)-4,5-dihydro-thiazol-2-ylamine dihydrochloride in the form of a pasty solid [1HNMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 3.20 to 3.40 (mt: 3H); from 3.60 to 3.80 (mt: 1H); 4.57 (mt: 1H); 7.85 (s, 1H); 9.10 (s: 1H); 9.26 (unresolved complex: 1H); 9.66 (unresolved complex: 1H); 10.13 (broad s: 1H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[K+].[Br-]>C(#N)C>[CH:18]1([C:21]([N:15]2[CH2:16][CH2:17][CH:12]([CH:9]3[C:10]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=4)[CH2:7][CH2:8]3)[CH2:13][CH2:14]2)=[O:22])[CH2:20][CH2:19]1
Reactant: COc1ccc2c(c1)C(C1CCNCC1)CC2
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2c(c1)C(C1CCN(C(=O)C3CC3)CC1)CC2
Reaction time: 72 h

Procedure:
A mixture of 4-(6-methoxy-indan-1-yl)piperidine (0.46 g, 2 mmol), cyclopropane carbonyl chloride (0.21 g, 2 mmol), and excess powdered potassium carbonate in acetonitrile was stirred for 72 h. The solution was filtered and concentrated in vacuo. The residue chromatographed on silica eluting with 2% methanol in methylene chloride to give, on concentration of the appropriate fractions, the product as an oil (0.5 g, 83%), IR (KBr) 2940, 1636, 1490, 1244, 1034 cm-1 ; H NMR (CDCl3, 300 MHz) δ 7.08 (d, 1H, J=7.9 Hz), 6.70-6.67 (m, 2H), 5.27 (m, 2H), 3.77 (s, 3H), 3.10-3.04 (m, 1H), 2.83-2.67 (m, 4H), 2.13-2.03 (m, 1H), 1.92-1.83 (m, 2H), 1.75-1.67 (m, 2H), 1.52-1.48 (m, 1H), 1.37-1.18 (m, 2H), 0.96-0.91 (m,2H). 0.73-0.67 (m, 2H). Anal. Calc'd for C19H25 NO2 ·0.2CH2Cl2 : C, 73.08%; H, 8.03%; N, 4.39%. Found: C, 72.81%; H, 7.94%; N, 4.44%.
Reaction SMILES: [N+:1]([C:4]1[C:5](C)=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([O-:9])=[O:8])([O-:3])=[O:2].[OH-].[K+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([OH:9])=[O:8])([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)[O-])c(C)c1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.6 %

Procedure:
To a 500 ml erlenmeyer flask with magnetic stirrer was charged 10.3 g of 3-nitro-4-methoxy-methylbenzoate, 400 ml tetrahydrofuran, and 3.2 g of 86% potassium hydroxide. The reaction was stirred for 12 hours at ambient temperature, after which the resulting solid was collected by vacuum filtration and washed with 2×100 ml of ethyl ether. The solid was dissolved in 200 ml of water and acidified to pH 4 with 6N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with 200 ml water, and dried overnight in vacuo at 30° C. Isolated 7.4 g of product as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([C:13](=[O:26])[C:14]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[C:16]([N+:23]([O-])=O)[CH:15]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]>[Pd].C1COCC1>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][N:6]([C:13](=[O:26])[C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[C:16]([NH2:23])[CH:15]=1)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:27])[CH3:12]
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc(N)cc(N)c1
Reaction time: 2.5 h
Yield: 97.6 %

Procedure:
A mixture of 5.95 g of N-(3,5-dinitrobenzoyl)-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester and 0.75 g of 10% palladium on carbon in 75 ml of THF was shaken under an initial hydrogen pressure of 54 psi in a Parr Hydrogenator until uptake ceased after 2.5 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to give 4.9 g of N-(3,5-diaminobenzoyl)-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester as a yellow oil. The mass spectrum was compatible with the structure.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([C:20]5[O:21][CH:22]=[CH:23][CH:24]=5)[CH2:15]4)[CH:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:30]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH3:30])[CH:16]([C:20]5[O:21][CH:22]=[CH:23][CH:24]=5)[CH2:15]4)[CH:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(c4ccco4)C3)c(F)cc2c1=O
Reactant: C=O
Solvent: O=CO
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1c1ccco1

Procedure:
A mixture of 200 mg of 1-cyclopropyl-6-fluoro-7-[3-(2-furanyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.3 ml of 90% formic acid and 0.24 ml of 37% formalin was heated for 2 hours, then evaporated. The residue was diluted with water, neutralized to pH 7 with 1N sodium hydroxide, the solid collected and washed with water, methanol and ether and dried in vacuo, giving 145 mg of the desired product, mp 122°-124° C.
Reaction SMILES: O.[NH2:2][NH2:3].[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](SC)=[C:14]([C:17]#[N:18])[C:15]#[N:16])=[CH:9][CH:8]=1)([O-:6])=[O:5]>CO>[NH2:16][C:15]1[NH:3][N:2]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([N+:4]([O-:6])=[O:5])=[CH:8][CH:9]=2)[C:14]=1[C:17]#[N:18]
Reactant: NN
Reactant: CSC(=C(C#N)C#N)c1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: O
Product: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)n[nH]c1N
Reaction time: 8 h

Procedure:
0.05 ml (1.00 mmol) of hydrazine hydrate is added dropwise to 245.3 mg (1.00 mmol) of 3-(4-nitrophenyl)-3-methylmercapto-2-cyano-acrylonitrile in 1.3 ml of methanol and the reaction mixture is then boiled for 8 hours and then concentrated by evaporation. The residue is stirred with ethyl acetate and filtered, yielding 5-amino-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile; TLC: Rf =0.14 (ethyl acetate:hexane=1:1).
Reaction SMILES: N[C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=O.[CH:14]1([NH:22][C:23]([NH2:25])=[S:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([NH:22][C:23]2[S:24][CH:2]([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=3)[C:3](=[O:5])[N:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC(=S)NC1CCCCCCC1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: O=C1N=C(NC2CCCCCCC2)SC1Cc1ccc(O)cc1

Procedure:
Synthesis was performed from (2S)-2-amino-3-(4-hydroxyphenyl)propanoic acid and N-cyclooctylthiourea according to Method E and C.
Reaction SMILES: [OH:1][C@H:2]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[N:30][C:31]([O:34]C)=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[C@H:3]([CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=[N:10]1)[C:4]([OH:6])=[O:5].B(Br)(Br)Br.C(OCC)(=O)C.O>C1(C)C=CC=CC=1>[OH:1][C@H:2]([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[N:30][C:31]([OH:34])=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)[C@H:3]([CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=[N:10]1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(-c2ccc(CC[C@@H](O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cn1
Agent: BrB(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H](CCn1nnc2ccccc2c1=O)[C@H](O)CCc1ccc(-c2ccc(O)nc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the compound obtained from Example 1A above (0.2 g) in dry toluene (5 mL), cooled to 78° C., boron tribromide (0.5 mL) was added and the contents were stirred at room temperature for 4 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain a residue which was purified by preparatory thin layer chromatography (2 mm thickness) using 15% methanol in dichloromethane as eluent to get the title compound (60 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH2:14][CH2:15][O:16][CH3:17])[C:6]=2[N:18]=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[O:29][CH3:30].C(O)C>Cl.O>[CH3:30][O:29][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:20]=1[NH:19][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH2:14][CH2:15][O:16][CH3:17])[C:6]=2[N:18]=1)[C:24]([OH:26])=[O:25]
Reactant: COCCN1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COCCN1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)O)cc3OC)nc21
Yield: 68.5 %

Procedure:
A mixture of 0.108 g (0.0004 mole) of 2-chloro-9-(2-methoxy-ethyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-40), 0.08 g (0.00048 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.11 g of 3-methoxy-4-[9-(2-methoxy-ethyl)-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-benzoic acid (I-40a) as an off-white solid.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][CH:28]=3)[C:10](=[O:22])[NH:11]2)[C:6]([OH:31])=[C:5]1[C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(C#N)cc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1ccc(C2C=C3C(=CN(Cc4ccccc4)C(C(=O)NCCC(=O)O)=C3O)NC2=O)cc1
Temperature: 25 °C
Yield: 118.3 %

Procedure:
A mixture of 1-benzyl-3-(4-cyano-phenyl)-5-hydroxy-2-oxo-1,2-dihydro-[1,7]-naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.097 mmol), β-alanine (694 mg, 7.8 mmol) and NaOMe solution (11.7 mL, 5.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude solid obtained was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 27 mg of the title compound. MS: (−) m/z 467.24 (M−1).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:4][CH2:3]1.[NH2:17][OH:18]>C(O)C>[OH:18][N:17]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:4][CH2:3]1
Reactant: O=C1CCC(COC(=O)N2CCCC2)CC1
Reactant: NO
Solvent: CCO
Product: O=C(OCC1CCC(=NO)CC1)N1CCCC1

Procedure:
To a solution of pyrrolidine-1-carboxylic acid 4-oxo-cyclohexylmethyl ester (2 mmol) in ethanol (10 mL) was added hydroxylamine (10 mmol) and the mixture was refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide pyrrolidine-1-carboxylic acid 4-hydroxyimino-cyclohexylmethyl ester. Pyrrolidine-1-carboxylic acid 4-hydroxyimino-cyclohexylmethyl ester was dissolved in a 2N ammonia methanol solution (10 mL) and then Raney nickel was added. After 12 hours stirring under hydrogen atmosphere, the reaction mixture was filtered and concentrated under reduced pressure to provide pyrrolidine-1-carboxylic acid 4-amino-cyclohexylmethyl ester. To a solution of pyridine-2-yl-methanol (2 mmol) in THF (10 mL) was added CDI (2 mmol). After 2 h stirring at room temperature, pyrrolidine-1-carboxylic acid 4-amino-cyclohexylmethyl ester was added and the resulting mixture was stirred for additional 2 hours at 60° C. The reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate), thereby completing the preparation of a target compound (310 mg, 43% yield).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].Br[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(OCC)(=O)C>O1CCCC1.O>[N:2]1([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C1CNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCC1
Reaction time: 0.17 h

Procedure:
A solution of azetidine hydrochloride (1 g, Aldrich) in a mixture of tetrahydrofuran (20 ml) and water (5 ml) was added with 2 N aqueous sodium hydroxide (10.7 ml) at 0° C., and then gradually added with tert-butyl bromoacetate (1.052 ml), and the mixture was stirred at the same temperature for 10 minutes, and further stirred at room temperature for 45 minutes. The reaction mixture was added with water and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate, the combined organic layer was washed three times with saturated brine, and the solvent was evaporated under reduced pressure to obtain the title compound (688 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:19][C:20]1[C:21](=[O:39])[N:22]([CH2:34][C:35]([O:37]C)=[O:36])[C:23]([CH3:33])=[CH:24][C:25]=1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH3:33][C:23]1[N:22]([CH2:34][C:35]([OH:37])=[O:36])[C:21](=[O:39])[C:20]([NH:19][S:15]([CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:17])=[O:16])=[C:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COC(=O)Cn1c(C)cc(Cc2ccccc2)c(N)c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Cc2ccccc2)c(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.6 %

Procedure:
1 ml (7.17 mmol) of triethylamine and 0.95 g (5 mmol) of (phenylmethyl)sulphonyl chloride are added to 1 g (3.5 mmol) of methyl 3-amino-6-methyl-2-oxo-4-(phenylmethyl)-1,2-dihydropyridine-1-acetate in solution in 30 ml of dichloromethane and the mixture is kept stirred for 12 hours at room temperature. The reaction medium is washed successively with 10 ml of water, 10 ml of a 1 N aqueous hydrochloric acid solution and then 10 ml of a saturated sodium chloride solution. The medium is dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a silica gel column, eluting with a dichloromethane:methanol (98:2) mixture. The product is used as such in the hydrolysis stage which is carried out according to the procedure described in Example 3. 0.8 g of product is obtained in the form of a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C1N2CN3CN(C2)CN1C3.O.C(O)(=[O:24])C>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
7.9 g of p-cyanobenzylamine, 8.4 g of hexamethylenetetramine, 40 ml of water, 20 ml of acetic acid and 50 ml of toluene were mixed and reacted at 90° C. for 2 hours while stirring. The reaction solution was cooled to room temperature and the toluene layer was separated, washed with water and concentrated until crystals were precipitated. The concentrated toluene solvent was placed in water, the toluene was removed by azeotropic distillation, and the residue was cooled to room temperature. The crystals precipitated were collected by filtration, washed with water and dried to obtain 4.8 g (yield: 60%) of p-cyanobenzaldehyde. The purity was 99.5% or more.
Reaction SMILES: [Na].CO.[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[N+:14]([CH:17]([CH3:19])[CH3:18])([O-:16])=[O:15]>C(O)(=O)C>[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]([OH:11])[C:17]([CH3:19])([N+:14]([O-:16])=[O:15])[CH3:18])=[CH:8][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C(O)C(C)(C)[N+](=O)[O-])cc1
Temperature: 13 °C
Reaction time: 0.42 h
Yield: 13.1 %

Procedure:
11.5 g of sodium are added to 300 ml of anhydrous methanol, and 67 g of 4-methoxybenzaldehyde and 105 g of 2-nitropropane are added thereto at 13° C. for 25 minutes under stirring. The mixture is stirred at 23° C. for 70 hours. 32 g of acetic acid are added to the mixture under ice-cooling, and said mixture is evaporated under reduced pressure to remove solvent. About 200 ml of water are added to the residue, and the aqueous mixture is extracted with benzene. The extract is washed with a saturated sodium chloride solution, a saturated sodium bisulfite solution, water and a saturated sodium chloride solution, successively. The washed extract is dried and then evaporated to remove solvent. The residue (yellow oil, 65 g) is distilled at 75° C. under reduced pressure (1-2 mm Hg) to recover 47 g of the starting compound (i.e., 4-methoxybenzaldehyde). On the other hand, 14.5 g of 1-(4 -methoxyphenyl)-2-methyl-2-nitropropanol (crude product) are obtained as the residue.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:29])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.I[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:29])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1)[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(N2CCOCC2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1ccc(N2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
A solution of diisopropylamine (344 μL, 2.45 mmol) in dry tetrahydrofuran (2.9 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (981 μL, 2.45 mmol). The reaction mixture was stirred at −78° C. for 15 min and then treated dropwise with a solution of (4-morpholin-4-yl-phenyl)-acetic acid methyl ester (549.9 mg, 2.34 mmol) in dry tetrahydrofuran (2 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The resulting reaction mixture was allowed to stir at −78° C. for 30 min, at which time, a solution of iodomethylcyclopentane (540.0 mg, 2.57 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 67 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid methyl ester (381.4 mg, 51%) as a white solid: mp 68-70° C.; EI-HRMS m/e calcd for C19H27NO3 (M+) 317.1991, found 317.2001.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].C(O)C.ClCCl.[O-2].[Mn+2]>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2ccc(Cc3ccccc3)cc2c1Cl
Agent: [Mn+2]
Agent: [Pd]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2ccc(Cc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 74.7 %

Procedure:
A mixture of crude ethyl 6-benzyl-4-chloroquinoline-3-carboxylate (B, 2.77 g), 10% palladium on activated carbon (0.28 g) and triethylamine (2.8 mL) in ethanol (30 mL) was stirred under a hydrogen atmosphere at room temperature for 19 hr. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with water and extracted with dichloromethane. The organic layer was washed with 10% citric acid, saturated sodium hydrogen carbonate, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane then dichloromethane:ethyl acetate=50:1 to 20:1, v/v) to afford overreduced compound. The hydroquinoline was dissolved in dichloromethane (30 mL) and activated manganese oxide (0.9 g) was added to the solution. After stirring at room temperature for 20 hr, the mixture was filtered through celite and concentrated in vacuo to afford the title compound (1.85 g) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.45 (t, J=6.8 Hz, 3H), 4.19 (s, 2H), 4.47 (q, J=6.8 Hz, 2H), 7.20-7.38 (m, 5H), 7.63-7.72 (m, 2H), 8.97 (d, J=8.8 Hz, 1H), 8.76 (d, J=1.5 Hz, 1H), and 9.39 (d, J=1.5 Hz, 1H); mass spectrum (EI+) m/e 291 (M+); (FAB+) m/e 292 (M+1).