Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][C:17]([CH2:22][OH:23])([OH:21])[CH2:16]1>CO>[OH:21][C:17]1([CH2:22][OH:23])[CH2:18][CH2:19][CH2:20][CH:15]([C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[OH:4])[CH2:16]1
Reactant: COCOc1ccc(C2CCCC(O)(CO)C2)c(OCOC)c1
Solvent: CO
Product: OCC1(O)CCCC(c2ccc(O)cc2O)C1
Yield: 23.6 %

Procedure:
(±)-3-[2,4-Bis(methoxymethoxy)phenyl]-1-(hydroxymethyl)cyclohexanol (29 mg), methanol (2 ml) and acidic ion exchange resin (300 mg) were heated under reflux for 3 hr. The reaction mixture was filtered and the resin was washed with methanol. The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to furnish the title compound as a cream solid (5 mg, 24%). δH(CD3OD) 1.20-2.00 (8H, m), 2.89 (1H, tt), 3.61 (1H, d), 3.69 (1H, d), 6.20-6.26 (2H, m), 6.90 (1H, d); m/z (ES−) 237 (M−H)−.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[CH3:17].[CH:18]([C:21]1[NH:22][CH:23]=[CH:24][N:25]=1)([CH3:20])[CH3:19]>CN(C=O)C>[CH:18]([C:21]1[N:22]([CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH3:17])[CH:23]=[CH:24][N:25]=1)([CH3:20])[CH3:19]
Reactant: Cc1cc([N+](=O)[O-])ccc1OCCCCl
Reactant: CC(C)c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1OCCCn1ccnc1C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.8 %

Procedure:
To a stirred solution of 50% sodium hydride (200 mg, 4 mmol) in DMF (5 mL) at 0° C. was added a solution of 1-(3-chloro-propoxy)-2-methyl-4-nitro-benzene (700 mg, 3 mmol) in dry DMF (3 mL). To this was added a solution of 2-isopropyl imidazole (300 mg, 3 mmol) in DMF (4 mL). The mixture was allowed to warm to r.t. and stirred for 5 hours. The mixture was poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water and brine then dried over sodium sulfate. Concentration in vacuo gave a residue which was purified by column chromatography on silica gel, eluting with 20% methanol in chloroform to afford 2-isopropyl-1-[3-(2-methyl-4-nitro-phenoxy)-propyl]-1H imidazole (380 mg, 41%) as an oil.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([CH2:14][O:15]C(=O)C)[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([NH:19][CH3:20])[S:10]2)[C@H:6]1[O:21]C(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:15][CH2:14][C@H:13]1[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([NH:19][CH3:20])[S:10]2)[CH:6]([OH:21])[C@@H:5]1[OH:4]
Reactant: CNC1=N[C@@H]2[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]2S1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CNC1=N[C@@H]2C(O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3aR,5R,6S,7R,7aR)-5-(acetoxymethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl diacetate (150 g, 417 mmol) in methanol (1 L) was treated with potassium carbonate (11.5 g, 83 mmol). The resulting mixture was stirred overnight at room temperature to yield a solid. This was collected by filtration, washed with cold methanol and dried. The product 24 was obtained as a yellow solid (85 g, 87%). (ES, m/z): [M+H]+ 235.1; 1H NMR (300 MHz, D2O) δ 6.14-6.16 (d, J=6.3 Hz, 1H), 4.03-4.07 (m, 1H), 3.89-3.92 (m, 1H), 3.65-3.70 (m, 1H), 3.48-3.56 (m, 2H), 3.41-3.45 (m, 1H), 2.69 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[NH:27])[NH:25][OH:26])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[N:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:34](Cl)=O>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:27]=[C:34]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][N:28]=4)[O:26][N:25]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: N=C(NO)N1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: O=C(Cl)c1cnccn1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2noc(-c3cnccn3)n2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-N-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide and pyrazine-2-carbonyl chloride following a procedure analogous to that described in Example 47. LC (method 2): tR=1.15 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(F)ccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(F)ccc1Cl)C2

Procedure:
To a solution of 7-(2-chloro-5-fluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one in ethanol (10 ml) were added aminoguanidine hydrochloride (0.041 g), concentrated hydrochloric acid (0.078 ml) and water (0.078 ml), and the mixture was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate, and to the aqueous layer was added sodium hydrogen carbonate solution to make it alkaline. The solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 1N hydrochloric acid (1 ml) and concentrated to give crystals, which were recrystallized from ethanol-ethyl acetate to give 7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 170) (0.05 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]([OH:28])=O)=[CH:9]2.[CH2:29]([S:36][C:37]1([CH2:43][NH2:44])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CCCCCC.C(OCC)(=O)C.CN(C)C=O>[CH2:29]([S:36][C:37]1([CH2:43][NH:44][C:26]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=3[N:15]([CH3:25])[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:18])=[O:28])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Reactant: NCC1(SCc2ccccc2)CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC3(SCc4ccccc4)CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.0 g), 1-[4-(benzylthio)tetrahydro-2H-pyran-4-yl]methanamine (0.65 g), 1H-1,2,3-benzotriazol-1-ol (0.44 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.62 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=20:80-80:20) to give the title compound (1.4 g, yield 90%) as a white solid.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:19].N([O-])=O.[Na+].NC(N)=O>O.[Cu-]=O>[OH:19][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)C(C)n1ncc2ccc(N)cc21
Agent: O=[Cu-]
Agent: NC(N)=O
Agent: O=N[O-]
Solvent: O
Product: CCOC(=O)C(C)n1ncc2ccc(O)cc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Ethyl 2-(6-aminoindazol-1-yl)propionate (0.49 g) was stirred with hot 35% sulphuric acid (2.12cm3), ice (2.12 g) added and the mixture cooled in an ice/salt bath. Sodium nitrite (0.187 g) in water (2cm3) was added dropwise at 0° C. The mixture was stirred for 5 minutes at 0° C. and a few crystals of urea added. Hydrated copper (II) nitrate (8 g) in water (74cm3) was then added followed by copper (I) oxide (0.3 g) and the mixture stirred for 15 minutes at 0° C. and 1.5 hours at hours at room temperature. The reaction mixture was extracted with ethyl acetate four times, the combined organic extracts washed with water, dried (MgSO4), filtered and the filtrate concentrated under vacuum. The residue was purified by chromatography (SiO2, diethyl ether; then hexane: diethyl ether, 35:65) to give ethyl 2-(6-hydroxyindazol-1-yl)propionate (30 mgs)
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[Cl:10][C:11]1[C:12]([NH2:18])=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1>>[NH2:18][C:12]1[C:11]([Cl:10])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:17][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Nc1cccc(Cl)c1N
Reactant: Cc1cscc1N=C=S
Product: Cc1cscc1NC(=S)Nc1cccc(Cl)c1N

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 3-chloro-1,2-diaminobenzene (prepared by catalytic hydrogenation of 3-chloro-2-nitroaniline using Pt on activated carbon under atmospheric pressure at room temperature). Crystalline solid, m.p. 298-305° C.,
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][CH2:31][CH2:32][C:33]([O:35]C)=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1.[OH-].[Na+].O.C(O)(=O)C>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)CCCC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cn3)CC2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCCC(=O)O)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
To a solution of methyl 4-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]butyrate (210 mg) in methanol (10 mL) was added a 3N aqueous sodium hydroxide solution (1.4 mL) at room temperature. After stirring the solution at room temperature for 3 hours, a 3N aqueous sodium hydroxide solution (0.7 mL) was added thereto at room temperature. The solution was stirred at room temperature for 2 hours. Water (5 mL) and acetic acid (0.36 mL) were then added to the solution and it was concentrated under reduced pressure to distill off the methanol. The solution was extracted with 20% ethanol/chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (180 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH3:14][NH:15][CH3:16]>CN(C)C=O>[CH3:14][N:15]([CH3:16])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc([N+](=O)[O-])cc1

Procedure:
4.9 g (20 mmol) of 4-(2-bromoethyloxy)-nitrobenzene and 2.7 g (60 mmol) of dimethylamine in 50 ml of dimethylformamide are heated to 100° C. for 24 hours in a bomb tube. After removal of the solvent in vacuo the residue is taken up in water and extracted with dichloromethane. The organic phase is dried and concentrated by evaporation.
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(=O)=O.[CH2:15]([C:22]1([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:15]([C:22]1([OH:28])[CH2:27][CH2:26][N:25]([CH2:5][CH2:6][C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: CS(=O)(=O)CCC#Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1(Cc2ccccc2)CCN(CCC#Cc2ccccc2)CC1
Yield: 30.4 %

Procedure:
A mixture of 1-mesyl-4-phenylbut-3-yne (300 mg, 1.34 mmol), 4-benzyl-4-hydroxypiperidine (307 mg, 1.61 mmol) and K2CO3 (555 mg, 4.02 mmol) in 15 mL of CH3CN is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×20 ml). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as an off-white solid (130 mg, 30%): mp 80-82° C; 1H NMR (CDCl3) 1.50 (m, 3 H), 1.74 (m, 2 H), 2.41 (m, 2 H), 2.58 (m, 3 H), 2.75 (m, 5 H), 7.11-7.38 (m, 10 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[CH3:25][C:26]1([NH:30][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([NH:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])[CH:16]=2)=[O:23])[CH2:29][O:28][CH2:27]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)n(C)n1
Reactant: CC1(N)COC1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NC2(C)COC2)n(C)n1
Yield: 28 %

Procedure:
As described for example 144, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using 3-methyl-oxetan-3-yl-amine instead of 2-hydroxy-2-methylpropylamine, to the title compound (17 mg, 28%) which was obtained as a white solid. MS: m/e=400.3 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11].C(N(CC)CC)C>ClCCl>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:11][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: COC(CN)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCC(OC)OC
Reaction time: 4 h
Yield: 65 %

Procedure:
Over a period of 4 hours, 104.5 parts of methacryloyl chloride dissolved in 105 parts of dichloromethane are added dropwise at a maximum of 15° C., while cooling with ice, to 105.14 parts of aminoacetaldehyde dimethylacetal and 101.2 parts of triethylamine in 200 parts of dichloromethane. When the reaction is complete, the dichloromethane phase is washed with 200 parts of water then with 200 parts of 1N HCl solution, and then twice with 200 parts of water. After drying with anhydrous magnesium sulfate, the dichloromethane phase is concentrated by evaporation and stabilised with 0.1% of 2,6-di-tert-butyl-p-cresol, based on the reaction product. After distillation at 90° C. 10-3 mbar, 112 g of methacrylamidoacetaldehyde dimethylacetal are obtained in the form of a colourless liquid, boiling point 92° C. 10-3 mbar (65% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[O:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[N:12][CH:13]=[CH:14][N:15]=1)=O.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:32]1([CH2:1][C:3]2[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=2)[O:6][CH2:7][CH2:8][O:9][C:10]2[C:11]([N:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21]3)=[N:12][CH:13]=[CH:14][N:15]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2cccc(C=O)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2cccc(CN3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
A stirred solution of the aldehyde from step 3 above (71.2 mg, 0.166 mmol) in 1,2-dichloroethane (5 mL) was treated with morpholine (19 mg, 0.22 mmol), 3 Å molecular sieves and sodium triacetoxyborohydride (52 mg, 0.25 mmol). The mixture was stirred at room temperature for 5 h (TLC monitoring). The solution was filtered and the filtrate was treated with an excess of saturated aqueous sodium bicarbonate. The ether extracts were separated and dried over magnesium sulfate. The mixture was filtered and solvent was removed in vacuo to give 54 mg (65%) of the title product as a yellow oil. Pure by NMR. 1H NMR (CDCl3) δ 1.4 (s, 9H); 2.35 (m, 4H); 3.4 (m, 10H); 3.65 (m, 4H); 4.3 (m, 2H); 4.65 (m, 2H); 6.75 (d, 1H); 6.9 (m, 2H); 7.2 (t, 1H); 7.5 (s, 1H); 7.7 (s, 1H).
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]1[C:11]([CH2:12][C:13]#[N:14])=[CH:10][CH:9]=[CH:8][N:7]=1)#[N:5].[C:15]([O:20][CH3:21])(=[O:19])/[CH:16]=[CH:17]/[CH3:18]>C(O)(=O)C>[CH3:18][CH:17]([CH:12]([C:13]#[N:14])[C:11]1[C:6]([C:4]#[N:5])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:16][C:15]([O:20][CH3:21])=[O:19]
Reactant: C/C=C/C(=O)OC
Reactant: N#CCc1cccnc1C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CC(C)C(C#N)c1cccnc1C#N

Procedure:
A catalytic amount of a 5% strength methanolic sodium methylate solution is added to a mixture of 4.9 g (0.03 mol) of 2-cyano-3-pyridylacetonitrile and 3.4 g (0.03 mol) of methyl crotonate with stirring at a rate such that the reaction temperature remains below 40° C. When the evolution of heat has subsided, the mixture is neutralized using dilute acetic acid. The mixture is extracted with chloroform and the organic phase is dried over MgSO4, filtered and concentrated in vacuo. The residue is purified over a silica gel column using chloroform as eluent.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])([O-:14])=[O:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: O=C1CCCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C(=Cc2cccc([N+](=O)[O-])c2)CCc2ccccc21

Procedure:
A mixture of 3,4-dihydro-1(2H)-naphthalenone (21.9 g), 3-nitrobenzaldehyde (22.6 g) and p-toluenesulphonic acid monohydrate (50 mg) in toluene (250 ml) was stirred at reflux with separation of water for 4.5 hours. The brown solution was allowed to cool overnight, the resultant orange-yellow solid filtered off, washed with toluene and dried in vacuo to give 2-(3-nitrobenzylidene)-3,4-dihydro-1(2H)-naphthalenone as yellow needles.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([NH2:11])=[CH:3][CH:2]=1.Br[N:13]1[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15](Br)[C:14]1=[O:22].CC1(C)NC(=O)NC1=O>[Cu]=O.CC(N(C)C)=O>[NH2:11][C:4]1[CH:3]=[CH:2][C:1]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]2=[O:22])=[CH:6][C:5]=1[C:7]([F:9])([F:10])[F:8]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ccccc1C(F)(F)F
Agent: O=[Cu]
Agent: CC1(C)NC(=O)NC1=O
Solvent: CC(=O)N(C)C
Product: CC1(C)NC(=O)N(c2ccc(N)c(C(F)(F)F)c2)C1=O
Reaction time: 0.5 h
Yield: 174.6 %

Procedure:
100 g of O-trifluoromethylaniline is introduced at 20°±2° C. then 100 ml of dimethylacetamide is added while maintaining the same temperature. After cooling down under agitation at 0° C.±2° C. a solution of 88.8 g of dibromodimethylhydantoin and 100 ml of dimethylacetamide is then added over about 30 minutes while maintaining the temperature at 0° C.±2° C. The reaction medium is maintained under agitation for 30 minutes, then taken to 20° C.±2° C. and 40 g of dimethylhydantoin then 50 g copper oxide are added. The whole is heated under reflux for approximately 18 hours then cooled down to 20° C.±2° C., agitation is carried out for 30 minutes followed by filtering, separating and washing with 4×25 ml of dimethylacetamide. The resultant product is then poured into 300 ml of pure 22°Be ammonium hydroxide and 300 ml of demineralized water under agitation over 1 hour at 20° C.±2° C., agitation is continued for 1 hour at 20° C.±2° C. then the whole is cooled down to 0° C.±5° C. and is maintained under agitation for another hour, followed by separating, washing at 20° C.±2° C., with 100 ml of pure 22°Be ammonium hydroxide then with 4×100 ml of demineralized water and drying. In this way 155.8 g of expected product is obtained.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]3[O:39][CH2:38][C:37](=[O:40])[N:36]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:35]=3[CH:46]=2)=[CH:12][CH:11]=1)(O)=[O:8]>ClCCl.CN(C)C=O>[Cl:4][C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]3[O:39][CH2:38][C:37](=[O:40])[N:36]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:35]=3[CH:46]=2)=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(C(=O)O)cc3)cc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(C(=O)Cl)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.190 ml of oxalyl chloride are added dropwise to a solution of 0.600 g of tert-butyl 4-(4-carboxyphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 6 ml of dichloromethane. The reaction solution is subsequently stirred at room temperature over 1 hour and then admixed with 2 drops of N,N-dimethylformamide and stirred at room temperature for a further 35 minutes. The reaction mixture is concentrated by evaporation to dryness and used further as the crude product without purification. Reddish oil, Rt=5.50.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH:7]1[CH2:12]CC[CH2:9][O:8]1)=[N+:2]=[N-:3].[CH3:13]C1(C)OC(COS(C2C=CC(C)=CC=2)(=O)=O)CO1>>[N:1]([CH2:4][CH:5]1[CH2:9][O:8][C:7]([CH3:12])([CH3:13])[O:6]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Product: CC1(C)OCC(CN=[N+]=[N-])O1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 408, using toluene-4-sulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (37.8 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 20:80 as the eluent to afford the title compound as colourless foam.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl>CCO>[CH:5]1[C:4]2[C:7]3[CH2:8][NH:3][CH2:4][CH2:5][C:6]=3[N:3]3[C:8]=2[C:7]([CH2:6][CH2:5][CH2:4]3)=[CH:7][CH:6]=1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: c1cc2c3c(c1)c1c(n3CCC2)CCNC1
Temperature: 25 °C
Yield: 298.5 %

Procedure:
1,2,3,4-Tetrahydroquinoylamine (0.925 g, 6.25 mmol) and 4-piperidone monohydrate hydrochloride (0.960 g, 6.25 mmol) were dissolved in EtOH (15 mL). Conc. HCl (0.52 mL, 6.25 mmol) was added. The reaction was refluxed for 3 hrs and then cooled to RT. The precipitate was collected by vacuum filtration. The residue was washed with 5 mL of EtOH, to afford the title compound (1.32 g, 85%) as a pure, white powder. 1H NMR (CD3OD, 300 MHz) δ7.22 (d, 1H, J=8.1 Hz), 6.92-6.97 (m, 1H), 6.86 (d, 1H, J=7.2 Hz), 4.87 (s, 2H), 4.05 (t, 2H, J=6.0 Hz), 3.61 (t, 2H, J=6.0 Hz), 3.14 (t, 2H, J=6.0 Hz), 2.94 (t, 2H, J=6.3 Hz), 2.16-2.24 (m, 2H) ppm.