Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][CH2:10][C:11]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:26])[C:13]=3[CH:12]=2)=[O:7])[CH:5]=[CH:4]N=[CH:2]1.N1CCC[CH2:29][CH2:28]1>CN(C)C=O>[N:1]1([C:6]([O:8][CH2:9][CH2:10][C:11]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:26])[C:13]=3[CH:12]=2)=[O:7])[CH2:2][CH2:29][CH2:28][CH2:4][CH2:5]1
Reactant: O=C1c2ccccc2C(=O)c2cc(CCOC(=O)n3ccnc3)ccc21
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)c2cc(CCOC(=O)N3CCCCC3)ccc21
Temperature: 0 °C
Yield: 43 %

Procedure:
To the solution dissolved 12.1 g of N,N′-carbonyldiimidazole (75 mmol; produced by Wako Pure Chemical Industries, Ltd) into 50 mL of dehydrated dimethylformamide (dehydrated DMF), 15.8 g of 2-anthraquinonyl-1-ethylalcohol (62 mmol) obtained by the same method as Synthetic Example 5 was added, then, the solution was reacted by stirring for 1 hour at room temperature. After completing reaction, ice-water was poured into the reaction solution, and this mixed solution was extracted with toluene, and further after organic layer after extraction was washed with water, the organic layer was condensed. The resultant condensed residue was purified with column chromatography (Filler: Silica-gel (Wako-gel C-200; produced by Wako Pure Chemical Industries, Ltd.), Developing solvent: ethyl acetate/n-heptane=1/9) to obtain 12.3 g of 2-anthraquinonyl-1-ethyl 1-imidazolylcarboxylate (yield: 57%) as yellow crystal. Subsequently, to the solution dissolved the resultant crystal of 2-anthraquinonyl-1-ethyl 1-imidazolylcarboxylate into 50 mL of dehydrated dimethylformamide (dehydrated DMF), 4.2 g of piperidine (50 mmol) was added, then, the solution was reacted for 1 hour at room temperature. After completing reaction, ice-water was poured into the reaction solution, this mixed solution was extracted with toluene, and further, organic layer after extraction was washed with water, the organic layer was condensed. The resultant condensed residue was purified with column chromatography (Filler: Silica-Gel (Wako-Gel C-200; produced by Wako Pure Chemical Industries, Ltd.), Developing solvent: ethyl acetate/n-heptane=1/9) to obtain 9.8 g of 2-anthraquinonyl-1-ethyl piperidinecarboxylate (yield: 43%) represented by the above-described formula [12] as yellow crystal. Measurement results of 1H-NMR and melting point are shown as the follows:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:15][S:16][C:17](S(C)=O)=[CH:18][N+:19]([O-:21])=[O:20]>CO>[CH3:15][S:16][C:17]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][CH:9]=[CH:8][N:7]=1)=[CH:18][N+:19]([O-:21])=[O:20]
Reactant: CCOc1cccnc1CSCCN
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Solvent: CO
Product: CCOc1cccnc1CSCCNC(=C[N+](=O)[O-])SC
Reaction time: 8 h
Yield: 49.2 %

Procedure:
2-(2-Aminoethylthiomethyl)-3-ethoxypyridine (2.2 g) in methanol (35 cc) was added over 25 minutes to a stirred solution of 1-methylthio-1-methylsulphinyl-2-nitroethylene (2.07 g) in methanol (85 ml) at 27°-30°, and the mixture was left overnight at room temperature. The mixture was evaporated to a residual oil which was triturated with ethanol/ether to give 1-methylthio-1-[2-(3-ethoxy-2-pyridylmethylthio)ethylamino]-2-nitroethylene (1.68 g) m.p. 126°-127°.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH3:22])[C:10]1=[O:23])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[F:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[F:21])[N:11]([CH3:22])[C:10](=[O:23])[N:9]([OH:8])[C:18]2=[O:19]
Reactant: Cn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Yield: 98.4 %

Procedure:
Twenty percent Pd/C (0.2 g) was added to a solution of 3-benzyloxy-6,7-difluoro-1-methyl-1H-quinazoline-2,4-dione (Example K, 1.55 g, 4.9 mmol) in 25 mL of THF and 25 mL of methanol. The mixture was shaken under 50 PSI of hydrogen for 1.5 hours, and filtered. The catalyst was rinsed with 200 mL of a 50/50 mixture of THF and methanol and concentrated to afford 1.1 g of the title compound as a solid, mp 239-241° C.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:15][N:16]([CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:27]=2)[CH:22]=[CH:21]1)[CH3:17]>C(O)(=O)C>[C:1]1([C:22]2[C:23]3[C:28](=[CH:27][C:26]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[N:20]([CH2:19][CH2:18][N:16]([CH3:17])[CH3:15])[CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN(C)CCn1ccc2ccc(-c3cccnc3)cc21
Reactant: O=C1CCCCC1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCn1cc(C2=CCCCC2)c2ccc(-c3cccnc3)cc21
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
In a 20 mL vial equipped with a screw cap and a stir bar was added cyclohexanone (0.1 mL; 0.88 mmol), trifluoroacetic acid (1 mL) and acetic acid (0.75 mL). The mixture was heated at 110° C. under argon for 15 minutes. A solution of compound (a), above, (0.07 g; 0.25 mmol) in acetic acid (1 mL) was added. The resulting mixture was stirred for an additional 20 minutes at 110° C. The reaction mixture was quenched with potassium hydroxide (1N) (pH: 10; 80 mL) and extracted with ethyl acetate (30 mL). The organic phase was successively washed with water (3×30 mL), brine (30 mL), dried (sodium sulfate), filtered and solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using chloroform:methanol (95:5) to yield the title compound (0.6 g; 64%). 13C NMR (CDCl3): δ148.6, 147.8, 138.0, 137.3, 134.5, 131.5, 130.9, 125.9, 123.5, 122.5, 121.8, 118.9, 118.4. 107.8, 45.8, 44.8, 34.2, 28.6, 25.8, 23.2, 22.5.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[CH2:8](Br)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:8]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])[CH2:9][CH2:10][CH3:11]
Reactant: CC(=O)CC(C)=O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC(C(C)=O)C(C)=O
Reaction time: 48 h
Yield: 55.4 %

Procedure:
2,4-pentanedione (205.4 ml, 2.0 mol), acetone (100 ml), n-butyl bromide (54 ml, 0.5 mol), and potassium carbonate (34.55 g, 0.25 mol) were fed into a reaction vessel, air in the vessel was replaced with nitrogen, and reflux was carried out for 48 hours. The resultant solid was filtered out, and the solvent was distilled off by means of an evaporator. After that, unreacted 2,4-pentanedione was distilled off under reduced pressure by means of a diaphragm. Then, the remainder was distilled in a vacuum to yield 3-n-butyl 2,4-pentanedione (43.25 g, 55% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20]CC)=[O:19].[OH-].[Na+]>CCO>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)C)c2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cccc(OCC(C)C)c2c(N)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of ethyl 4-amino-5-isobutoxy-2-methylquinoline-3-carboxylate (Example 41a, 18.0 g, 59.53 mmol) in EtOH (150 mL) was added aqueous NaOH solution (3 N, 50 mL) and the reaction mixture was refluxed overnight. It was then cooled down to room temperature and the solution was filtered to remove any possible solid residue. The filtrate was carefully neutralized with 6N HCl to pH 7 at 0° C. The resultant precipitate was collected by filtration, washed with water, re-dissolved in EtOH (700 mL) and water (20 mL), and treated with activated charcoal (650 mg) at 70° C. for 0.5 h. The charcoal was removed by filtration, and the filtrate was concentrated and stored at 4° C. overnight. The resulting precipitate was collected by filtration, washed with cold H2O, and dried under vacuum at 60° C. overnight to give the title compound as a white solid (4.24 g, 26%). M.p.: 203.7° C. 1H NMR (400 MHz, DMSO-d6) δ 1.01-1.02 (m, 6H), 2.19-2.24 (m, 1H), 2.77 (s, 3H), 4.05 (d, J=6.4 Hz, 2H), 7.08 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H), 8.9 (brs, 1H), 11.45 (brs, 1H), 13.2 (brs, 1H). MS 275 (MH+). Elemental Analysis Calculated (Found) for C15H18N2O3.0.75H2O: C, 62.59%; (62.23%); H, 6.83%; (7.25%); N, 9.76%; (9.73%).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>C(Cl)(Cl)Cl>[CH2:14]([N:16]([CH2:17][CH3:18])[C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[N:10][C:2]=1[CH3:1])[CH3:15]
Reactant: Cc1ncc([N+](=O)[O-])cc1C(=O)O
Reactant: CCNCC
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1cc([N+](=O)[O-])cnc1C

Procedure:
In dry chloroform were dissolved 0.3 g of 2-methyl-5-nitronicotinic acid and 1.5 ml of diethylamine. After addition of 10 g of phosphorous pentaoxide, the mixture was stirred with heating at 55° - 60° C. for 3 hours. After cooling, the chloroform portion was separated and evaporated under reduced pressure. The residue was, after addition of water, neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The extract was concentrated and purified on a silica gel column to give 0.25 g of a colorless oil.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[S:13](=[O:15])(=[O:14])[N:12]([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([N:30]1CCNS1(=O)=O)C1C=CC=CC=1>>[ClH:1].[CH2:2]([N:9]1[S:13](=[O:15])(=[O:14])[N:12]([C:16]2[CH:17]=[CH:18][C:19]([NH:20][NH2:30])=[CH:21][CH:22]=2)[CH2:11][CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)S2(=O)=O)cc1
Reactant: O=S1(=O)NCCN1Cc1ccccc1
Agent: Cl
Product: NNc1ccc(N2CCN(Cc3ccccc3)S2(=O)=O)cc1

Procedure:
The title compound was prepared from 4-(5-benzyl-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)aniline hydrochloride by a similar method to that described for Intermediate 1 (step 1); pale brown solid; δH (250 MHz, DMSO-d6) 7.42-7.32 (5H, m, Ph), 7.24 (2H, d, J=8.5 Hz, Ar--H), 7.02 (2H, d, J=8.5 Hz, Ar--H), 4.24 (2H, s, PhCH2 --), 3.68 (2H, t, J=6.4 Hz, --CH2 --), 3.39 (2H, t, J=6.4 Hz, --CH2 --).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([N+:13]([O-])=O)[CH:9]=[CH:10][C:11]=1[Cl:12]>C(O)C.Cl.O.[OH-].[Na+]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[Cl:12])[NH2:13]
Reactant: CN(C)CCOc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)CCOc1cc(N)ccc1Cl

Procedure:
A solution of 3-(2dimethylaminoethoxy)-4chloronitrobenzene (D57) (295 mg) in ethanol (5 ml) was heated to 60° C. and treated dropwise with a solution of stannous chloride (0.82 g) in concentrated hydrochloric acid (1.5 ml) with stiring. After heating to reflux for 1/2 h, the reaction mixture was cooled, diluted with water and basified with 40% NaOH, then extracted into dichloromethane. The dried (Na2SO4) organic phase was evaporated under reduced pressure to give the title compound as a yellow oil. (221 mg, 85%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:22][C:23](O)=O)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[N:9]=2)[C:4]1=[O:21])[CH3:2].[NH4+].O[N:28]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C=O>[CH2:1]([C:3]1([CH2:22][C:23]#[N:28])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[N:9]=2)[C:4]1=[O:21])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCC1(CC(=O)O)CCN(c2ccnc(Nc3cnn(C)c3)n2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(CC#N)CCN(c2ccnc(Nc3cnn(C)c3)n2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of (3-ethyl-1-(2-((1-methyl-H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-oxopyrrolidin-3-yl)acetic acid (100 mg) obtained in Example 30 and 1-hydroxybenzotriazole ammonium salt (88 mg) in N,N-dimethylformamide (5 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (110 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the residue and pyridine (70 mg) in tetrahydrofuran (5 mL) was added trifluoroacetic anhydride (0.12 mL), and the mixture was stirred at 70° C. for 30 min. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (17 mg).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)=[O:13])[CH:6]=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:24]=1
Reactant: [H][H]
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCC(O)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(O)CC3)c2)c(F)c1
Reaction time: 2 h

Procedure:
4-(2-Fluoro-4-nitrophenoxy)-2-[(4-hydroxypiperidin-1-yl)carbonylamino]pyridine (169 mg) was dissolved in methanol (5 ml)-tetrahydrofuran (5 ml), and then 10% palladium carbon (200 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring for 2 hrs. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with ethyl acetate. The filtrate was concentrated under a reduced pressure to provide the titled compound (168 mg, quantitatively) as pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].C([Li])CCC.CCCCCC.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24]>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][C:23](=[O:24])[C:22]([F:29])([F:28])[F:21])[CH3:2]
Reactant: CCOC(=O)C(F)(F)F
Reactant: C#CC(OCC)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(C#CC(=O)C(F)(F)F)OCC
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
3,3-Diethoxy-1-propyne (10 mL, 70 mmol) was dissolved under argon in THF (200 mL) and cooled to −70° C. Then a 1.6 M solution of n-butyllithium in hexane (48 mL, 77 mmol) was added slowly at −70° C., then allowed to warm to −30° C. and stirred at −30° C. for 30 min, then cooled again to −70° C. Ethyl trifluoroacetate (9.2 mL, 77 mmol) was added in one portion at −70° C. (the temperature rose to −50°) then stirred without cooling until −30° C. was reached, then quenched with sat. NH4Cl solution (20 mL). Extraction: 2×AcOEt, 1× sat. NH4Cl sat., 1× sat. NaCl. Chromatography on silica gel in heptane/ethyl acetate 5:1 afforded 4.94 g (31%) of an orange oil. GC/MS: m/z=223 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=2)[C:7]=1[CH3:8].[OH-].[Na+].C(O)(=O)C>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=2)[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1cn2c(C)c(Br)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(Br)ccc2nc(C(=O)O)cn12
Yield: 76.5 %

Procedure:
To a solution of 0.283 g of ethyl 6-bromo-5-methylimidazo[1,2-a]pyridine-2-carboxylate in 2 mL of ethanol is added 1 mL of 1 N sodium hydroxide. The reaction mixture is refluxed for 3 hours. After cooling, the reaction medium is acidified with acetic acid. The solid formed is filtered off, washed with water and then dried under vacuum to give 0.195 g of 6-bromo-5-methylimidazo[1,2-a]pyridine-2-carboxylic acid in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([Br:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH2:6][S:7]2.Cl.[CH3:15][O:16][NH2:17].C(O)C>N1C=CC=CC=1>[CH3:15][O:16][N:17]=[C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[C:11]([Br:12])[C:2]=2[CH3:1])[S:7][CH2:6][CH2:5]1
Reactant: Cc1c(Br)ccc2c1C(=O)CCS2
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CCSc2ccc(Br)c(C)c21
Yield: 93.2 %

Procedure:
3.0 Grams (12 mmol) of 5-methyl-6-bromothiochroman-4-one and 1.9 g (23 mmol) of O-methylhydroxylamine hydrochloride were refluxed under heat in a mixed solvent containing 10 ml of ethanol and 10 ml of pyridine for 30 minutes. The solvents were distilled off under reduced pressure, and then 50 ml of 5% hydrochloric acid was added to form a solid. The solid was recovered by filtration, washed with water and dried to give 3.2 g of 4-methoxyimino-5-methyl-6-bromothiochroman (yield 93%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][CH:3]=1.N1([C:18](N2C=CN=C2)=[S:19])C=CN=C1>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]=[C:18]=[S:19])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)c2ccccc12
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: S=C=Nc1ccc(Br)c2ccccc12
Reaction time: 16 h

Procedure:
To a solution of 1-bromo-4-aminonapthalene (2.6 g, 12 mmol) in dichloromethane (45 mL) was added di(1H-imidazol-1-yl)methanethione (2.1 g, 12 mmol). The reaction was allowed to stir for 16 h, at which point the reaction was concentrated to give a gray solid. The solid was slurried in 50% EtOAc/hexanes and filtered through a pad of silica gel, rinsing with 400 mL 50% EtOAc/hexanes. The solution was concentrated to give 1-bromo-4-isothiocyanatonaphthalene as a gray solid, which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 7-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine (2.33 g) in dry DCM (120 ml, TEA (4.2 ml 2.5 eq), BOC2O (6.1 g, 2.3 eq.), DMAP (296 mg, 0.2 eq.) were added. The mixture was stirred at rt. for 1 h then the solvent was evaporated in vacuo. The material thus obtained was purified by flash chromatography over silica gel (eluting with 20% ethyl acetate in hexane) to give the title compound (3.25 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH:18]([NH:21]C(=O)[O-])[CH2:17]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.O.[OH-].[Na+]>C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C([O-])NC1CCN(CCCOCCc2ccc3sccc3c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: NC1CCN(CCCOCCc2ccc3sccc3c2)C1

Procedure:
In 7.0 mL of ethyl acetate was dissolved 1.12 g of tert-butyl=1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinylcarbamate, and 1.86 mL of 6 mol/L hydrochloric acid was added to the solution, after which the resulting mixture was heated under reflux for 1 hour. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 10 with a 2 mol/L aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform:methanol=30:1 to 20:1) to obtain 0.38 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinamine as a light-yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:7]1)C.[OH-].[Na+].Cl.C1(C)C=CC=CC=1>C(O)C>[Cl:20][C:17]1[S:16][C:15]([C:13]([NH:12][CH:8]2[CH2:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:21])=[O:3])[CH2:7]2)=[O:14])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CN1CCCC(NC(=O)c2ccc(Cl)s2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)CN1CCCC(NC(=O)c2ccc(Cl)s2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
9.2 To a stirred solution of {3-[(5-chloro-thiophene-2-carbonyl)-amino]-piperidin-1-yl}-acetic acid ethyl ester at r.t. in 5 ml ethanol were added 5 ml 1 N NaOH. The slurry slowly turned to a clear solution. Stirring at r.t. was then continued for 5 h. The mixture was neutralized by adding 5 ml of 1 N HCl (pH ˜7). The light orange solution was concentrated to leave an off-white solid. This residue was coevaporated several times with toluene to remove the remaining H2O, and dried overnight (r.t., 0.5 mbar) to give 1.07 g {3-[(5-chloro-thiophene-2-carbonyl)-amino]-piperidin-1-yl}-acetic acid (containing 2 mol equivalents of sodium chloride). Off-white solid. MS 301.3 ([M−H]−)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)Nc3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 1-fluoro-4-isocyanatobenzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 7.45 (q, 2H, J=4.7 Hz), 7.23 (m, 4H), 7.05 (t, 4H, J=7.8 Hz), 6.75 (m, 1H), 4.05 (m, 1H), 3.19 (s, 1H), 2.71 (m, 1H), 2.53 (m, 1H), 2.25 (m, 3H), 1.8 (m, 9H), 1.25 (d, 6H, J=6.4 Hz); ESMS m/e: 441.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH2:11]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(S)cc1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(SCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-aminothiophenol (6.0 g) was dissolved in methanol (120 ml), aqueous solution of sodium hydroxide (2.7 g, 36 ml) was added to the mixture, benzyl bromide (6.8 ml) was added to the mixture at 0° C., and the mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure, and the obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 4-(benzylsulfanyl)aniline (7.0 g).