Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22]CO)[N:18]=[C:17]([O:25][CH3:26])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(NC2N=C(Cl)N=C(OC)N=2)CC1)=O)(C)(C)C.CN.C(N(C(C)C)C(C)C)C.COC1N=C(NC2CCNCC2)N=C(NCCO)N=1>C(#N)C>[CH3:26][O:25][C:17]1[N:18]=[C:19]([NH:21][CH3:22])[N:20]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:16]=1
Reactant: COc1nc(NCCO)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: CN
Agent: COc1nc(Cl)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: COc1nc(NCCO)nc(NC2CCNCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1nc(NC2CCNCC2)nc(OC)n1

Procedure:
The compound was prepared in analogy to the synthesis of 4-[4-(2-hydroxy-ethylamino)-6-methoxy-[1,3,5]triazin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (intermediate C26/step 2) from 4-(4-chloro-6-methoxy-[1,3,5]triazin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (intermediate C26/step 1) and methylamine (12 M solution in water) and N-ethyl diisopropylamine in acetonitrile at rt, followed by BOC cleavage in analogy to the procedure described for 2-[4-methoxy-6-(piperidin-4-ylamino)-[1,3,5]triazin-2-ylamino]-ethanol (intermediate C26/step 3). MS (ISP): 239.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH2:5][CH2:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH:9]([O:12][CH2:13][CH2:14][OH:15])[C:10]=2[N:11]=1.C(P(CCCC)CCCC)CCC.[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:34].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1C=CC=CC=1.O>[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:15][CH2:14][CH2:13][O:12][CH:9]2[C:8]3[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=3[CH2:6][CH2:5][C:4]3[O:3][C:2]([CH3:1])=[N:11][C:10]2=3)=[CH:41][CH:40]=1)[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: Cc1nc2c(o1)CCc1ccccc1C2OCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3CCc3oc(C)nc32)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.1 %

Procedure:
Under a nitrogen atmosphere, 2-(2-methyl-9,10-dihydro-4H-1-oxa-3-aza-benzo[f]azulen-4-yloxy)-ethanol (400 mg, 1.6 mmol), tributylphosphine (480 mg, 2.4 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (380 mg, 1.6 mmol) were successively dissolved in dry benzene (10 mL). Solid azodicarboxylic dipiperidine (ADDP) (480 mg, 2.4 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. The mixture was added water and the product extracted with ethyl acetate. The combined organic phases was dried (MgSO4), and concentrated in vacuo. The residue was purified chromatography eluting with petroleum ether/ethyl acetate (1:1) to give 300 mg (40%) of the title compound: 1H NMR (300 MHz, CDCl3) δ1.15 (t, 3H). 1.20 (t, 3H), 22.38 (s, 3H), 2.60-2.85 (m, 2H), 2.90-3.05 (m, 3H), 3.25-3.38 (m,1H), 3.52-3.65 (m, 1H), 3.65-3.75 (m, 1H). 3.75-3.90 (m, 2H), 3.95 (t, 1H), 4.05 (t, 2H), 4.15 (q, 2H), 5.25 (s, 1H), 6.75 (d, 2H), 7.10 (d, 2H), 7.13-7.30 (m, 4H).
Reaction SMILES: Cl.[CH3:2][CH2:3][O:4][CH2:5][CH3:6].CCN(CCO)C[CH2:11][N:12]1[C:16]2[C:17]([N:19]([CH3:24])C(N(C)C=2[N:14]=[C:13]1[CH2:25][C:26]1C=CC=CC=1)=O)=O.Cl>CCOCC>[N:12]1[CH:13]=[CH:25][CH:26]=[C:2]([CH2:3][O:4][C:5]2[N:14]=[C:13]([N:12]3[CH2:11][CH2:24][NH:19][CH2:17][CH2:16]3)[CH:25]=[CH:26][CH:6]=2)[CH:11]=1
Reactant: CCN(CCO)CCn1c(Cc2ccccc2)nc2c1c(=O)n(C)c(=O)n2C
Reactant: CCOCC
Agent: Cl
Product: c1cncc(COc2cccc(N3CCNCC3)n2)c1
Reaction time: 8 h

Procedure:
A solution of 2-bromo-6-(pyridin-3-ylmethoxy)-pyridin-hydrochloride prepared as above (25.07 g, 94.6 mmol) was suspended in 275 mL of dry dioxane and then 65.06 g (756.5 mmol, 8 equiv.) of piperazine and 14.19 g (94.6 mmol) of NaI were added. The reaction mixture was then heated slowly to reflux under an atmosphere of dry N2. After about 1 h, the solids in the reaction mixture went partially into solution. Reflux was continued for 48 h at which time the reaction mixture was cooled and taken up in cold water, giving a pale yellow solution. This was extracted four times with ethyl acetate and the combined extracts were backwashed once with water and washed with saturated NaCl solution. The organic solution was dried with MgSO4 and the solvent was evaporated to give 20.7 g of pale yellow oil. This oil was dissolved in 500 mL of dry ether and stirred rapidly while 75 mL of 1 M HCl/ether solution was added dropwise (the mixture was seed with a small amount of mono-HCL salt prepared earlier by the same procedure on smaller scale). The HCl salt crystallized and was granulated overnight at room temperature under N2 atmosphere. The crystalline salt was filtered off and washed with dry ether and dried in a stream of dry N2 and residual ether was removed by pumping in high vacuum for 5 h to give 21.67 g (75%) of off white solid, m.p.=141–143° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:35])([F:34])[C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH:19]([CH3:29])[C:20]([O:27][CH3:28])=[CH:21][C:22](OCC)=[O:23])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[H-].O>CCOCC>[F:7][C:8]([F:34])([F:35])[C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH:19]([CH3:29])[C:20]([O:27][CH3:28])=[CH:21][CH2:22][OH:23])=[CH:16][CH:15]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COC(=CCO)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a slurry of LiAlH4 (400 mg) in anhydrous ether (20 ml) is added dropwise at 0°, a solution of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoate (1.2 g) in ether (10 ml). After addition is complete, the reaction mixture is stirred for about 10 minutes. Excess hydride is decomposed with wet ether and water. After filtration, the filtrate is concentrated to give the alcohol, 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-penten-1-ol.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[OH:17][C:18]1[N:23]=[N:22][C:21]([C:24](O)=O)=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.O>CO>[CH2:14]([N:7]1[C:8](=[O:9])[C:10]2[NH:13][C:24]([C:21]3[N:22]=[N:23][C:18]([OH:17])=[CH:19][CH:20]=3)=[N:12][C:11]=2[N:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:6])[CH2:15][CH3:16]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)c1ccc(O)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(O)nn3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 1,3-dipropyl-5,6-diaminouracil (2.2 mmol) in methanol was added an equimolar amount of 6-hydroxy-pyridazine-3-carboxylic acid, followed by a slight excess of DCl ((N-(3-(dimethylamino)propyl)-N′ethylcarbodiimide hydrochloride). The mixture was stirred at room temperature for 4-5 hours until complete by TLC. Water was then added and the precipitate removed by filtration. The solid was dissolved in 10% aqueous NaOH (20 mL), then heated at 70° C. for 30 minutes. After cooling to room temperature, the reaction mixture was acidified to pH=5 with 10% hydrochloric acid and the precipitated product collected by filtration.
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]([C:21]([N+:24]([O-])=O)=[CH:22][CH:23]=2)[CH:15]=[CH:16][C:17](OC)=[O:18])[CH2:8][CH2:7]1)=[O:4].[H][H]>C(O)C.[C].[Pd]>[CH3:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:21](=[CH:22][CH:23]=2)[NH:24][C:17](=[O:18])[CH2:16][CH2:15]3)[CH2:8][CH2:7]1)=[O:4]
Reactant: CCC(=O)NC1CCN(c2ccc([N+](=O)[O-])c(C=CC(=O)OC)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)NC1CCN(c2ccc3c(c2)CCC(=O)N3)CC1

Procedure:
1.25 Grams of methyl 3-[4-(N-methylacetylamino)1-piperidyl]-6-nitrocinnamate was dissolved in 50 ml of ethanol, then 0.4 g of 10%-palladium carbon was added thereto, the reaction mixture was stirred until the absorption of hydrogen gas was stopped under conditions of at room temperature and normal pressure. The catalyst was removed by filtration, the filtrate was concentrated by evaporating the solvent, the residue thus obtained was purified by means of a silica gel column chrmatography (eluent: dichloromethane:methanol=50:1), then recrystallized from methanol-diethyl ether to yield 0.82 g of 6-[4-(N-methylacetylamino)-1-piperidyl]-3,4-dihydrocarbostyril. Light yellow needle-like crystals. Melting point: 195°-197° C.
Reaction SMILES: COC(C1C=C(OC)C=C2OC(C)CC=12)=O.[CH3:17][O:18][C:19](=[O:31])[C:20]1[CH:25]=[C:24]([OH:26])[C:23]([CH2:27][CH:28]=[CH2:29])=[C:22]([OH:30])[CH:21]=1>[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[CH3:17][O:18][C:19]([C:20]1[CH:25]=[C:24]([OH:26])[C:23]2[CH2:27][CH:28]([CH3:29])[O:30][C:22]=2[CH:21]=1)=[O:31]
Reactant: C=CCc1c(O)cc(C(=O)OC)cc1O
Agent: [Zr+4]
Agent: COC(=O)c1cc(OC)cc2c1CC(C)O2
Agent: [Cl-]
Product: COC(=O)c1cc(O)c2c(c1)OC(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1d, from zirconium(IV) chloride and 4-allyl-3,5-dihydroxy-benzoic acid methyl ester (10b) (85 mg, 0.41 mmol). Purification by flash column chromatography eluting with 15-25% EtOAc in hexane gave a pale yellow solid (58 mg, 68% yield). 1H NMR (400 MHz, CDCl3) δ 7.17-7.21 (m, 2 H) 5.76 (s, 1 H) 4.42-4.51 (m, 1H) 3.91 (s, 3 H) 3.11-3.21 (m, 2 H) 1.60 (d, J=6.57 Hz, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([NH:11][C:12]([O:14]CC)=O)[CH3:10])=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:10])[NH:11][C:12](=[O:14])[NH:19][N:20]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)NC(C)C(=O)c1ccc(Br)cc1
Solvent: O
Solvent: CCCCO
Product: CC1NC(=O)NN=C1c1ccc(Br)cc1
Yield: 43.8 %

Procedure:
A mixture of 4'-bromo-2-ethoxycarbonylaminopropiophenone (4.29 g), hydrazine hydrate (8 g) and n-butanol (50 ml) was refluxed under heating for 68 hours. The solution was evaporated to dryness, and the resultant residue was dissolved in a mixture of chloroform and methanol. The solution was washed with water and the washings were extracted with chloroform. The combined organic layer was dried over magnesium sulfate and evaporated to dryness. The resultant residue was washed with diisopropyl ether and recrystallized from ethanol to give colorless crystals of 6-(4-bromophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.68 g), m.p. 213.5°~215° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([OH:10])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].[CH2:11]1[CH2:15][O:14][CH2:13]C1>>[C:1]([O:5][CH2:6][CH:7]([O:10][CH2:11][CH2:15][O:14][CH3:13])[CH2:8][O:9][CH2:2][CH2:1][O:5][CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)OCC(O)CO
Product: COCCOCC(COC(C)(C)C)OCCOC

Procedure:
Compound 21 (31.0 g, 0.135 mol.) was added to a slurry of the di-sodium salt of 3-tert-butoxy-1,2-propane diol, (0.062 mol.), 17, in refluxing in dry THF (500 ml). The reaction mixture was stirred, heated and maintained at reflux under an atmosphere of dry nitrogen for 24 hours. The mixture was allowed to cool and filtered and the solvent was removed by evaporation under vacuum. The residue was extracted with chloroform, dried (MgSO4) filtered and solvent removed by vacuum rotary evaporation to yield a brown liquid (17.0 g). The crude product was washed with water (250 ml) and extracted with chloroform (300 ml). The organic fraction was separated from the aqueous and dried (MgSO4) filtered. The solvent was removed by rotary evaporation under vacuum to give a pale yellow oil (15.0 g, 94%). The crude product was distilled (bpt. 120°-125° C., 0.25 torr) to give a colorless oily liquid (11.1 g, 67%): IR 2975, 2875 (CH) cm-1, 1198 (COC) cm-1, 1108 (COC) cm-1, 1H-NMR (CDCl3), d (ppm) 3.3-3.85 (m, 19H), 1.3 (s, 9H, tert-butyl), 13C-NMR (CDCl3), d, (ppm) 78.95, 72.94, 72.21, 71.92, 71.74, 70.64, 69.69, 61.73, 58.98, 58.8, 27.43. Mass spectroscopy, m/e: 264 M+ ; 208 (M-C(CH3)3)+ base peak.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH3:18])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Br)c(Cl)c1

Procedure:
To a suspension of 4-bromo-3-chlorobenzoic acid (5.00 g, 21.2 mmol) in ethanol (50 mL) was added sulphuric acid (5 mL) and the resultant mixture heated to reflux for 60 h. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with further ethyl acetate and the combined organic fractions dried (phase separator) and concentrated in vacuo to give the title compound as a brown oil/solid (5.09 g, 19.3 mmol). δH (d6-DMSO, 400 MHz): 8.06 (1H, d), 7.96 (1H, d), 7.80 (1H, dd), 4.33 (2H, q), 1.33 (3H, t).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][N:13]=1.C(N(CC)CC)C>C(O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[NH2:10])=[CH:14][N:13]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NN(Cc1ccc(Cl)nc1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of (4-fluorophenyl)hydrazine hydrochloride (2.52 g, 20 mmol; Aldrich) and 2-chloro-5-(chloromethyl)pyridine (3.24 g, 20.00 mmol; Aldrich) in ethanol (120 mL) was treated with triethylamine (9.76 mL, 70.0 mmol; Aldrich), and the mixture was heated at 80° C. with stirring for 16 hours. The solvent was removed and the residue was purified by flash chromatography (silica gel, 10:1 CH2Cl2—CH3OH) to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 4.53 (s, 2H), 6.93-6.99 (m, 2H), 7.02-7.10 (m, 2H), 7.40 (d, J=8 Hz, 1H), 7.77 (dd, J=8, 3 Hz, 1H), 8.30 (d, J=3 Hz, 1H); MS (DCI/NH3) m/z 252 (M+H)+.
Reaction SMILES: [C:1]([O:5][P:6]([C:13]([F:38])([F:37])[C:14]1[CH:36]=[CH:35][C:17]([CH2:18][CH:19]([C:31]([O:33][CH3:34])=[O:32])[NH:20]C(OCC2C=CC=CC=2)=O)=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl.CO>CO.[Pd]>[C:9]([O:8][P:6]([C:13]([F:38])([F:37])[C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH:19]([C:31]([O:33][CH3:34])=[O:32])[NH2:20])=[CH:35][CH:36]=1)([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)C(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C(N)Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Yield: 60 %

Procedure:
A solution of benzyloxycarbonyl-protected 11 (45 mg, 0.081 mmol) in MeOH (0.8 mL) is stirred at ambient temperature under 1 atm of H2 over 10% Pd C (9 mg). After 2.5 hours the reaction mixture is filtered through silica gel and taken to dryness in vacuo to yield crude 12 quantitatively. Pure 12 (60% yield) can be obtained by silica gel chromatography [CHCl3 :MeOH(20:1)].
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:17]3=[O:41])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:42].[CH:43]1[C:48](O)=[CH:47][CH:46]=[C:45]([CH3:50])[CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(N=NC(OCC)=O)=O>C(OCC)(=O)C.C1COCC1>[CH3:50][C:45]1[CH:46]=[CH:47][C:48]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[C:10]([CH2:15][CH:16]4[S:20][C:19](=[O:21])[NH:18][C:17]4=[O:41])[CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:42])=[CH:43][CH:44]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C1CCc2c(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cccc2N1CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(OCCCN2C(=O)CCc3c(CC4SC(=O)NC4=O)cccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
A THF solution (2 ml) of 100 mg (0.18 mmol) of 5-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]-3-trityl thiazolidine-2,4-dione, 0.0363 ml (0.347 mmol) of p-cresol, and 91.1 mg (0.35 mmol) of triphenylphosphine was cooled with ice. 0.158 ml of azodicarboxylic acid diethyl (2.2 M toluene solution) was added to the solution in an argon atmosphere. The mixture was stirred at room temperature for two hours, and ethyl acetate was added to the reaction liquid. After washing with water, the organic layer was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure, and 2 ml of a solution of 4N-hydrogen chloride/ethyl acetate was added to the residue. The mixture was stirred at room temperature overnight, and further stirred at 70° C. for 1.5 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure and evaporated to dryness, giving 27.1 mg (34.4% yield) of 5-{1-[3-(4-methylphenoxy)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidine-2,4-dione as a colorless amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[C:7]([CH:9]1[CH2:14][CH2:13][N:12](C(C(F)(F)F)=O)[CH2:11][CH2:10]1)=[O:8])([O-:3])=[O:2].[N+](C1C=CC=CC=1C(C1CCN(C(C(F)(F)F)=O)CC1)=O)([O-])=O.[ClH:47]>C(O)(C)C>[ClH:47].[N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[C:7]([CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)C1CCN(C(=O)C(F)(F)F)CC1
Agent: Cl
Agent: O=C(c1ccccc1[N+](=O)[O-])C1CCN(C(=O)C(F)(F)F)CC1
Solvent: CC(C)O
Product: O=C(c1cccc([N+](=O)[O-])c1)C1CCNCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 100 %

Procedure:
4-(3-nitrobenzoyl)-1-trifluoromethylcarbonylpiperidine (4.9 g (0.0148 mol)) and 4-(2-nitrobenzoyl)-1-trifluoromethylcarbonylpiperidine (67:33) were added to isopropanol (100 mL) and HCl 37% (15 mL). The suspension was refluxed for 10 h to complete the hydrolysis. The reaction was monitored by TLC [silica gel/ethyl acetate-hexane (2:3)]. The resulting yellow solution was allowed to cool to room temperature and the resulting suspension was post-agitated for 10 h. The reaction mixture was then concentrated under reduce pressure and the residue was dried under vacuum for 16 h at 50° C. 4 g (100%) of 4-(3-nitrobenzoyl)piperidine HCl and 4-(2-nitrobenzoyl)piperidine HCl mixture were isolated as a light colored solid.
Reaction SMILES: C(O[Cl:6])(C)(C)C.[CH2:7]([CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=[O:17])[CH:8]=[CH2:9]>CO>[Cl:6][C:10]1([CH2:7][CH:8]=[CH2:9])[C:11](=[O:17])[CH2:12][CH2:13][CH2:14][C:15]1=[O:16]
Reactant: C=CCC1C(=O)CCCC1=O
Reactant: CC(C)(C)OCl
Solvent: CO
Product: C=CCC1(Cl)C(=O)CCCC1=O
Yield: 91.1 %

Procedure:
t-Butylhypochlorite (104.6 g, 0196 mol) was added dropwise to a solution of 2-allyl-1,3-cyclohexanedione (132 g, 0.87 mol) in 650 ml of methanol at 0° C. The temperature was not allowed to rise above 20° C. The methanol was removed at reduced pressure in a 40° water bath and the residual oil was taken up in benzene. The benezene solution was washed with 5 percent sodium thiosulfate (3 × 250 ml), 5 percent sodium bicarbonate (3 × 250 ml) and water (1 × 250 ml). Evaporation of the benzene gave 148 g (91 percent) of 2-chloro-2-allyl-1,3-cyclohexanedione as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:17]=[CH2:18])=[CH:8]2.B.[OH-:20].[Na+].OO>C1COCC1.O>[OH:20][CH2:18][CH2:17][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]=2[O:2][CH3:1])[CH:8]=1
Reactant: C=Cc1ccc2c(OC)c(OC)c(OC)cc2c1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2cc(CCO)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5,6,7-Trimethoxy-2-vinylnaphthalene (1.215 g) was dissolved in dry THF (10 mL) under an argon atmosphere, a THF solution (4.7 mL) of 1 M borane was added dropwise to the solution at 0° C., and the mixture was stirred at room temperature for 2 hours. Water (4 mL) was added to the reaction mixture at 0° C., and an aqueous solution (1.2 mL) of 4 M sodium hydroxide was then added. 31% Aqueous hydrogen peroxide (0.5 mL) was added to the reaction mixture at 0° C., and the mixture was stirred at 50° C. for 50 minutes. The reaction mixture was concentrated under reduced pressure, and water was added to the residue to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:8) to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:31]=1[CH2:32][NH2:33]>ClCCl>[CH3:39][O:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH3:28])[C:31]=1[CH2:32][NH:33][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COc1cccc(OC)c1CN
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1CNC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
4 g 2-nitrobenzoic acid (23.93 mmol) and 2.42 g triethylamine were dissolved in 100 mL dichloromethane, mixed with one equivalent isobutyl chloroformate (3.27 g) at 5° C. and stirring was continued for 1 hour at room temperature. Then the mixture was cooled again to 5° C., 4.02 g 2,6-dimethoxybenzylamine was added and the mixture was stirred at room temperature until the reaction was complete. For workup, the mixture was diluted with dichloromethane, washed twice each with 10% citric acid, saturated NaHCO3 and saturated NaCl solution, dried with MgSO4, filtered and concentrated, yielding 7.5 g beige solids that were reacted further directly without any further workup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[H-].[Na+].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1ccc2[nH]cc(CCN3CCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(CCN3CCCC3)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-3-(2-pyrrolidinylethyl)-1H-indole (Example 2, 9.10 g, 31 mmol) in tetrahydrofuran (100 mL) cooled to 0° C., were added sodium hydride (12.4 g, 310 mmol) and p-toluenesulfonyl chloride (6.10 g, 32 mmol). The resulting mixture was stirred at room temperature for 3 h, poured into water (200 mL) and extracted into ethyl acetate (200 mL). The organic phase was washed with water (200 mL) and then poured onto a silica gel column which was eluted with ethyl acetate followed by methanol. The title compound was obtained as a yellow syrup (11.7 g, 90%).