Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[O:10][CH:11]=[C:12]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][C:13]=23)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1OCCOCCOCCOCCOC1.[Br:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43](Cl)(=[O:45])=[O:44]>C1COCC1>[Br:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43]([N:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:12]2=[CH:11][O:10][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[C:13]12)(=[O:45])=[O:44]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: c1ccc(-c2occ3c2[nH]c2ccccc23)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1Br)n1c2ccccc2c2coc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.1 g (52.5 mmol) of NaH (60% in mineral oil) are dissolved in 500 ml of THF under a protective-gas atmosphere. 11.5 g (50 mmol) of 3-phenyl-4H-furo[3,4-b]indole and 11.5 g (52.5 mmol) of 15-crown-5 dissolved in 200 ml of THF are added. After 1 h at room temperature, a solution of 12.7 g (55 mmol) of 2-bromobenzenesulfonyl chloride in 250 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 18 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene and recrystallised from toluene/n-heptane. The yield is 16 g (75%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH3:22])=[CH:4][CH:3]=1.[CH:25](O)=[O:26]>C1(C)C=CC=CC=1>[CH:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH3:22])=[CH:23][CH:24]=1)=[O:26]
Reactant: O=CO
Reactant: COc1cc2c(cc1OC)C(C)N(CCc1ccc(N)cc1)CC2
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(C)N(CCc1ccc(NC=O)cc1)CC2
Yield: 100 %

Procedure:
To a stirred solution of N-(4-aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline (18.5 g, 0.056 m) in toluene (200 ml) under nitrogen was added 97% formic acid (25 ml) and the mixture heated to reflux, collecting the toluene insoluble material in a Dean-Stark tube. After 25 ml had been collected (ca 1 hr) the mixture was cooled and analyzed by TLC to insure completion. The mixture was poured into 500 ml H2O and basified to pH 11 with 10% NaOH, then extracted with CHCl3 (3×250 ml) and the combined extracts dried over MgSO4. Evaporation of the solvent gave N-(4-formamidophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline as an oil, 20.0 g (100% yield).
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O.[NH2:14][NH2:15].Cl.Cl.NN.O>C(O)CO>[Br:1][C:2]1[C:3]([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:14][NH:15][CH:11]=1
Reactant: Oc1nc2ccccc2cc1Br
Reactant: NN
Agent: Cl
Solvent: O
Solvent: OCCO
Product: Brc1c[nH]nc1Nc1ccccc1

Procedure:
The bromohydroxyquinoline (1.97 g, 8.79 mmol) was dissolved in 21 ml of ethylene glycol and hydrazine hydrate (4.2 ml) was added. To this mixture were added 1.3 g (12.2 mmol) of hydrazine dihydrochloride, and the resulting mixture was heated to reflux and stirred under nitrogen. The resulting material was poured onto 300 ml of H2O. The mixture was extracted with CH2Cl2, basified with NaHCO and extracted further with CH2Cl2. The combined organic portions were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to give a brown oil, yielding bromoanilinopyrazole (i.e., 3-(2-amino-5-bromophenyl)pyrazole).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[Li]C(CC)C.CN(CCN(C)C)C.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C1COCC1>[C:21]([Si:24]([CH:2]1[CH:1]=[CH:6][CH2:5][CH:4]=[CH:3]1)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:20]
Reactant: C1=CCCC=C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)C1C=CCC=C1
Temperature: -45 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
1,4,-Cyclohexadiene (3.76 mL, 40 mmol, 1 eq.) was dissolved in THF (64 mL) and cooled to −78° C. s-BuLi (40 mL, 44 mmol, 1.1 eq.) was added dropwise and the resulting suspension was treated with TMEDA (6.12 mL, 40 mmol, 1 eq.). The reaction mixture was allowed to warm to −45° C. over 2 hours, TBDMSCl (6.6 g, 44 mmol, 1.1 eq.) in THF (20 mL) was added dropwise and the reaction stirred at room temperature for 1 hour. The reaction was quenched with Et2O and H2O and then extracted with Et2O (3×100 mL). The combined organic layers were washed with sat. NH4.Cl (aq.) (100 mL) and brine (100 mL), dried over MgSO4 and the solvent removed in vacuo. Distillation using Kugelrohr apparatus (125° C., 43 mbar) afforded the product as a colourless oil (5.9 g, 31 mmol, 77% yield). 1H NMR (CDCl3) δ 5.74 (2H, m, H-5), 5.55 (2H, m, H-6), 2.70 (2H, m, H-7), 2.41 (1H, m, H-4), 0.95 (9H, s, H-1), 0.01 (6H, s, H-3); C13 NMR (100 MHz, CDCl3) δ 134.5 (C-4), 121.2 (C-5), 29.3 (C-4), 27.2 (C-7), 26.2 (C-1), 17.7 (C-2), −6.2 (C-3); IR (neat, cm−1) 3029 (m, C—H), 2956 (m, C—H), 1667 (w, C═C); MS (CI, m/z) 195.16 [M+H+].
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH:26][C@@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: c1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
3-Phenoxybenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[C:4]([F:19])[CH:3]=1.[Cl:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=2)[NH:23][N:22]=1.N=C=N>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:30][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[Cl:20])=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1
Agent: N=C=N
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(Cl)cc2F)CC(=O)N1
Yield: 6.4 %

Procedure:
The product from Example 3, Step 2 (103 mg, 0.36 mmol, 1.0 equiv) was combined with 3-chloro-1H-indazol-5-amine (91 mg, 0.54 mmol, 1.5 equiv) and PS-carbodiimide resin (0.994 mmol/g loading, 580 mg, 0.54 mmol, 1.5 equiv) in 6 mL of DMF and reacted overnight at room temperature. The reaction mixture was filtered and washed alternately with MeOH and CH2Cl2 (twice), then with diethyl ether. The filtrate was concentrated en vacuo and redissolved in EtOAc. The solution was washed with 0.5 N HCl, 0.5 N NaOH and satd. NaCl. The organic layer was concentrated en vacuo. Following purification by flash chromatography (0-50% EtOAc in CH2Cl2), the solid was triturated with CH2Cl2 to provide 10 mg (6.5%) of the title compound as light pink crystals. MS (ES+) m/e 434 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:34])[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:21])[CH3:34])=[CH:33][CH:32]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN(C)CCCOc1ccc(N)cc1
Product: CN(C)CCCOc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 4-(3-(dimethylamino)propoxy)aniline (21.6 mg, 0.12 mmol). The title compound was obtained as a solid (17.5 mg, 33% yield). MS m/z: 527.16, 525.16 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.Cl.[CH3:25][O:26][C:27]([C@H:29]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1)=[O:28]>>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([NH:11][C:9]2[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=[C:2]([NH:35][C@H:32]4[CH2:31][CH2:30][C@H:29]([C:27]([O:26][CH3:25])=[O:28])[CH2:34][CH2:33]4)[N:7]3[N:8]=2)=[O:19])[CH:14]=1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: COC(=O)[C@H]1CC[C@H](Nc2cc(C(F)(F)F)cc3nc(NC(=O)c4cccnc4)nn23)CC1

Procedure:
The title compound was prepared following procedure described for example 85, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and trans-4-amino-cyclohexylcarboxylic acid methyl ester hydrochloride (IRIS), 52 μl; 0.73 mmol; 5.0 eq.) as a white powder (23 mg, 34%). HPLC, Rt: 3.33 min. (purity 96.4%). LC/MS, M+(ESI): 463.1, M−(ESI): 461.1.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C@H:16]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:17][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH3:19])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C1COCC1>O>[OH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C@H:16]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:17][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH3:19])[CH2:11][CH2:10]1
Reactant: CN(C[C@H](C[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C[C@H](C[C@H]1CC[C@H](O)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 62.9 %

Procedure:
tert-Butyl (S)-1-(trans-4-(t-butyldimethylsilyloxy)cyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (18 g, 34 mmol) was treated with 4 M nBu4NF/THF (50 mL) at 50° C. for 6 h. Water (30 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give crude tert-butyl (S)-1-(trans-4-hydroxycyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (9 g, 64%) that was purified by silica chromatography. 1H NMR (CDCl3, 400 MHz) δ 1.41(d, 9 H), 1.65(m, 6 H), 1.95(m, 3 H), 2.98(d, 3 H), 3.10(m, 1 H), 3.52(m, 1 H), 3.90(m, 1 H), 5.13(d, 2 H), 7.33(m, 5 H).
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:16]1[O:27][C:26]2[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]=2[O:17]1>C1(C)C=CC=CC=1>[CH2:16]1[O:27][C:26]2[CH:25]=[CH:24][C:20]([C:21]([O:9][C:8]3[N:7]=[CH:6][NH:5][C:4]=3[C:1](=[O:3])[NH2:2])=[O:22])=[CH:19][C:18]=2[O:17]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC(=O)c1[nH]cnc1OC(=O)c1ccc2c(c1)OCO2
Reaction time: 4 h

Procedure:
To a mixture of 1.27 g of 4-carbamoylimidazolium-5-olate in 42.4 g of 10% aqueous solution of sodium carbonate was added 7.38 g of 3,4-methylenedioxybenzoylchloride in 20 ml of toluene at room temperature. After addition was over, the mixture was stirred for 4 hours. Then the separated crystals were filtered off, washed with water and toluene, dried in vacuo to give 5-carbamoyl-1H-imidazol-4-yl 3,4-methylenedioxybenzoate, m.p. 206.5°-208° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.Cl>C(#N)C>[N+:12]([C:11]1[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc2ccccc2nc1Cl
Reactant: Nc1ccc(O)cc1
Agent: Cl
Solvent: CC#N
Product: O=[N+]([O-])c1cc2ccccc2nc1Nc1ccc(O)cc1

Procedure:
A mixture of 2-chloro-3-nitroquinoline [0.35 g, prepared by the method of Kaneko, Chem. Pharm. Bull. (Tokyo) 7, 273 (1959)], 4-aminophenol (0.6 g), acetonitrile (20 ml) and dilute hydrochloric acid (30 ml, 1 M) was heated under reflux for 16 hours. The resulting deep orange solution was concentrated under reduced pressure (to 20 ml) and extracted with ethyl acetate (50 ml). The ethyl acetate extract was dried and evaporated to give 4-[N-(3-nitro-2-quinolinyl)amino]phenol as an organge solid, mp 190° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17][CH3:18].[OH-].[K+].O>CS(C)=O>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)c1
Temperature: 110 °C
Yield: 20.5 %

Procedure:
Step D (1): A mixture of 4-methyl-1H-imidazole (18.0 g, 53.5 mmol), 1-chloro-2-methoxy-4-nitrobenzene (10.0 g, 53.5 mmol), and potassium hydroxide (4.5 g, 80.3 mmol) in DMSO (50 mL) was heated at 110° C. for 24 h. The reaction mixture was allowed to cool to rt and was poured into 1000 mL of water. The aqueous mixture was extracted with dichloromethane (3×250 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (330 g silica cartridge, 0-2% MeOH/chloroform, linear gradient over 72 min, flow 25 mL/min) to afford 1-(2-methoxy-4-nitrophenyl)-4-methyl-1H-imidazole (2.56 g, 20% yield) as a yellow/orange solid. LC-MS (M+H)+=234.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.97-8.00 (m, 1 H) 7.93-7.97 (m, 2 H) 7.45 (d, J=8.85 Hz, 1 H) 7.02 (s, 1 H) 4.02 (s, 3 H) 2.35 (s, 3 H).
Reaction SMILES: [CH3:1]N(C)C1C=CC=CC=1.[C:10]([O:13][CH2:14][C:15]1[N:29]=[C:18]2[N:19]=[C:20]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:21]=[C:22]([OH:23])[N:17]2[N:16]=1)(=[O:12])[CH3:11].C(Cl)(Cl)Cl>P(Cl)(Cl)(Cl)=O>[C:10]([O:13][CH2:14][C:15]1([CH3:1])[N:29]=[C:18]2[N:19]=[C:20]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:21]=[C:22]([OH:23])[N:17]2[NH:16]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OCc1cc(O)n2nc(COC(C)=O)nc2n1
Reactant: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCC1=NC2=NC(C)(COC(C)=O)NN2C(O)=C1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
In 300 ml of phosphorus oxychloride was added dropwise 28 ml of N,N-dimethylaniline, and 30.5 g of 2,5-bis(acetoxymethyl)-7-hydroxy-s-triazolo[1,5-a]pyrimidine was added to the mixture and the mixture was stirred at 50 ° C. for 1.5 hours. An oily residue obtained by removing phosphorus oxychloride was dissolved in 500 ml of chloroform and ice-cooled. After addition of crushed ice and water to the mixture and stirring thereof, a chloroform layer was separated, washed with water and dried over anhydrous magnesium sulfate. Then, the mixture was condensed. This was applied to a silica gel column chromatography (eluent chloroform) and fractions containing the title compound were condensed to obtain 14 g of the title compound as an oily product.
Reaction SMILES: C1(C)C=CC=CC=1.[O:8]=[C:9]1[CH2:16][C:13]([CH3:15])([CH3:14])[CH2:12][C:11]([CH3:17])=[CH:10]1.[OH2:18]>[O-]S([O-])(=O)=O.[Cu+2].CCCCCC>[CH3:17][C:11]1[C:12](=[O:18])[C:13]([CH3:15])([CH3:14])[CH2:16][C:9](=[O:8])[CH:10]=1
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC1=CC(=O)CC(C)(C)C1=O
Reaction time: 90 h

Procedure:
A 1-1 three-neck flask equipped with a gas inlet frit, a stirrer and an intensive condenser was charged with 350 ml of toluene, 350 g of isophorone, 11.4 g of H3 [P(Mo3O10)4 ]×H2O, 1.4 g of CuSO4 ·5H2O and 1.4 g of MoO3. After compressed air had been passed through at 110° C. for 90 hours, the reaction mixture was added a little at a time at 80° C. into 4 1 of boiling n-hexane. The mixture was then filtered, and the filtrate was concentrated in a rotary evaporator. The yellowish oil obtained by distillation at 97° C./13 mbar was converted into almost colorless crystals at -18° C. by addition of 10% by volume of n-hexane.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[CH:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[C:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: Ic1ccccc1
Reactant: C#CCOCCn1c(COCC)nc2cnc3ccccc3c21
Product: CCOCc1nc2cnc3ccccc3c2n1CCOCC#Cc1ccccc1
Reaction time: 0.83 h
Yield: 78.5 %

Procedure:
Using the general method of Example 12 Part A, 2-(ethoxymethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (1.5 g, 4.13 mmol) was reacted with iodobenzene (0.51 mL, 4.54 mmol) at 40° C. After 50 minutes the reaction was judged complete. The volatiles were removed under reduced pressure and the resulting oil was partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The organic fractions were combined, washed with brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to leave a brown oil. The oil was purified by chromatography over silica gel (98/2 dichloromethane/methanol) to provide 1.25 g of 2-(ethoxymethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as a brown glassy solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1>S(Cl)(Cl)=O>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:12]([C:10]2[S:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][CH:9]=2)=[O:14])=[CH:26][C:25]=1[N:31]1[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]1
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2ccc(-c3ccccn3)s2)cc1N1CCN(C)CC1
Reaction time: 18 h
Yield: 66.6 %

Procedure:
5-(pyrid-2-yl)thiophene-2-carboxylic acid (0.279 g; 1.36 mmol) was heated at reflux in thionyl chloride (8 ml) for 1 hour, cooled, evaporated in vacuo and the residue azeotroped with toluene. The orange residue was redissolved in CH2Cl2 (10 ml) and treated with dry triethylamine (0.19 ml; 1.36 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.3 g;1.36 mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 2%MeOH/CHCl3 to yield the title compound as a orange gum (0.37 g;67%), which was converted to the oxalate salt, mp=131° C.(dec).
Reaction SMILES: [CH3:1]OC1C(OC)=CC2C(=O)CCCCC=2C=1.C[O-].[Na+].[CH3:20][O:21][C:22]1[C:23]([O:37][CH3:38])=[CH:24][C:25]2[C:31](=[O:32])[CH:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28][CH2:27][C:26]=2[CH:36]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:1][O:34][C:33]([CH:30]1[CH2:29][CH2:28][CH2:27][C:26]2[CH:36]=[C:22]([O:21][CH3:20])[C:23]([O:37][CH3:38])=[CH:24][C:25]=2[CH:31]1[OH:32])=[O:35]
Reactant: COc1cc2c(cc1OC)C(=O)C(C(=O)O)CCC2
Reactant: COc1cc2c(cc1OC)C(=O)CCCC2
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CCCc2cc(OC)c(OC)cc2C1O

Procedure:
Using 2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (10 g), powdery sodium methoxide [prepared by subjecting a 28% methanol solution of sodium methoxide (40 g) to concentration to dryness under reduced pressure] and dimethyl carbonate (150 g), a condensation reaction is carried out in a manner as that described in Example 42. The resulting methyl ester of 2,3-dimethoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylic acid is dissolved in a mixture of methanol (100 ml) and methylene chloride (100 ml). The solution is subjected to reduction in a manner as that described in Example 42, using sodium borohydride (2 g). The product is purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1) to afford 2,3-dimethoxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylic acid methyl ester (8 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].O.[C:6]1([C:12]([CH:14]=O)=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>O>[C:6]1([CH:12]2[CH2:14][NH:4][CH2:1][CH2:2][NH:3]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: c1ccc(C2CNCCN2)cc1
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
To a stirring solution of ethylenediamine (1.2 g, 20.0 mmol) in IMS (10 mL) was added a solution of phenylglyoxal hydrate (3.0 g, 20.0 mmol) in IMS (20 mL) dropwise. The resultant solution was stirred at room temperature for 3 hours and then sodium borohydride was added and the reaction mixture stirred over the weekend. Water (25 mL) was added and stirring continued for 15 minutes then the ethanol was removed by evaporation. A further amount of water (25 mL) was added and the solution was extracted with DCM (×3) then the combined organics were washed with brine, dried and the solvent evaporated. The material was purified by column chromatography using a silica II cartridge, eluting with 0-20% ammonia in methanol to afford 2-phenyl-piperazine as a pale yellow-orange solid (1.9 g). LCMS m/z 163.36 [M+H]+ R.T.=0.34 min (Analytical Method 6).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([NH2:12])[CH:10]=[CH2:11]>>[CH2:9]([N:12]=[CH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH:10]=[CH2:11]
Reactant: C=CCN
Reactant: O=Cc1ccncc1
Product: C=CCN=Cc1ccncc1

Procedure:
Pyridine-4-carboxaldehyde and 2-propenyl amine were reacted by the procedure of example 1(c) to afford the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>ClCCCl>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10]
Reactant: COCCOCCl
Reactant: Cc1cc(C=O)cc(C)c1O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1c(C)cc(C=O)cc1C

Procedure:
A mixture of 4-hydroxy-3, 5-dimethylbenzaldehyde (5 g), N, N-diisopropylethylamine (6.9 ml), (2-methoxyethoxy)methylchloride (4.26 ml) and 1, 2-dichloroethane (65 ml) was refluxed for 5 hours. The reaction mixture was washed with water and dried over magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate (8:2 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give 4-[(2-methoxyethoxy)methoxy]-3, 5-dimethylbenzaldehyde (6.54 g).