Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: CCOC(=O)CCCOc1ccccc1OCc1ccccc1
Yield: 47.8 %

Procedure:
To a stirred solution of 2-benzyloxyphenol (1) (4.0 g, 20 nM) and ethyl 4-bromobutyrate (2) (5.6 g, 28.7 mM) in dried acetone (100 mL) was added anhydrous ground potassium carbonate (6.0 g, 44 mM) and the resultant mixture heated at reflux under nitrogen until TLC analysis showed the absence of the starting phenol. Flash chromatography (silica gel, 15% ethyl acetate/hexane as eluant) of the filtered and concentrated mixture yielded 3.0 g of product (3) as a clear oil.
Reaction SMILES: C([O:5][C:6]([CH:8]=[CH:9][C:10]1[C:11](=[O:25])[C:12]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:13]=2[NH:14][C:15](=[O:19])[C:16]=1[O:17][CH3:18])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:12]2[C:11](=[O:25])[C:10]([CH:9]=[CH:8][C:6]([OH:7])=[O:5])=[C:16]([O:17][CH3:18])[C:15](=[O:19])[NH:14][C:13]=2[CH:20]=1
Reactant: COc1c(C=CC(=O)OC(C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C=CC(=O)O)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
4-[2-(Tert-butoxycarbonyl)ethenyl]-8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.3455 g) was dissolved in dry methylene chloride (7.5 mL) under argon. The solution was treated with trifluoroacetic acid (7 mL). The solution was stirred at room temperature for 30 minutes. The solution was concentrated under water aspirator vacuum and then it was dried under high vacuum to give a white solid. The solid was dissolved in 125 mL of hot methanol. The solution was filtered and concentrated to 80 mL volume as a white solid formed. It was cooled in an ice bath and the solid was filtered off, washed with cold methanol, and air-dried to give a white solid (0.162 g); mp 281.4°-282.0° C. (dec); 1H NMR (d6 -DMSO) 7.54 (d,1, J=16), 6.52 (d,1, J=16) for trans olefin protons; MS: m/z=308. Analysis for C14H10ClNO5 : Calculated: C, 54.65; H, 3.28; N, 4.55; Found: C, 54.36; H, 3.14; N, 4.37.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][N:18]([CH:26]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27]1)[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:25][C:22]1[CH:21]=[CH:20][C:19]([N:18]([CH3:17])[CH:26]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27]2)=[CH:24][CH:23]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CN1CCC(N(C)c2ccc(N)cc2)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCC(N(C)c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)C1
Yield: 43.2 %

Procedure:
(4E)-6-Bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.17 g, 0.61 mmol) and N-methyl-N-(1-methyl-pyrrolidin-3-yl)-benzene-1,4-diamine (0.12 g, 0.61 mmol) were stirred in N,N-dimethylformamide (3 mL) and triethylamine (0.16 mL) at 60-70° C. The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol, and then dried under vacuum to give (4Z)-6-bromo-4-[({4-[methyl(1-methylpyrrolidin-3-yl)amino]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione (0.12 g, 44%) as a rust colored powder.
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC=CC=1.[OH-].[Na+]>CN1CCCC1=O>[C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCCCCCC1
Reaction time: 2 h
Yield: 71.1 %

Procedure:
10.6 g of stabilized IBX prepared as in Example 10 are suspended in 60 ml of N-methylpyrrolidone at 20° C., and 2 g of cyclooctanol are added dropwise while maintaining the temperature at from 20° C. to 25° C. After 2 hours, agitation, the medium is poured into a mixture of 130 ml of water and 80 ml of toluene; the pH of the aqueous phase is brought to approximately 7 by the addition of aqueous NaOH and the organic phase, after separation of the insoluble material formed and of the aqueous phase, is concentrated to give 1.4 g of pure cyclooctanone (NMR and GPC)
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH2:12][CH2:13][NH:14][CH2:15][CH:4]2[C:3]1=[O:16].Cl.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.CC(C)=O.C(N(CC)CC)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH2:12][CH2:13][N:14]([CH2:24][C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[CH2:15][CH:4]2[C:3]1=[O:16]
Reactant: CN1C(=O)C2CNCCN2c2ccccc21
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1C(=O)C2CN(Cc3ccncc3)CCN2c2ccccc21

Procedure:
A solution of 6 g. (0.03 mole) of 2,3,4,4a-tetrahydro-6-methyl-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 5 g. (0.03 mole) of 4-picolyl chloride hydrochloride, 10 g. of potassium carbonate and 0.5 ml. of triethylamine was stirred and refluxed in 200 ml. of acetone overnight, cooled and filtered. The solvent was removed and the residue was dissolved in methylene chloride. This solution was washed with water and brine, dried over magnesium sulfate and filtered. The solvent was removed and the residue was chromatographed on 460 g. of Silicar, CC-7. Fractions eluted with 10% methanol in ethyl acetate afforded the product as a free base. This free base was dissolved in ethanol and treated with dry hydrogen chloride saturated ether. The product hydrochloride was filtered and recrystallized from methanol to yield 5.2 g. of the title compound as the dihydrochloride salt, m.p. 252°-254.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23]Br)[C:8]=1[CH2:25][CH2:26][CH3:27])[CH3:2].[OH:29][C:30]1[C:35]([CH2:36][CH2:37][CH3:38])=[C:34]([OH:39])[CH:33]=[CH:32][C:31]=1[C:40](=[O:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][O:39][C:34]2[CH:33]=[CH:32][C:31]([C:40](=[O:42])[CH3:41])=[C:30]([OH:29])[C:35]=2[CH2:36][CH2:37][CH3:38])[C:8]=1[CH2:25][CH2:26][CH3:27])[CH3:2]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCCOCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCOCCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 73.8 %

Procedure:
A mixture of 1.89 g (0.004 mole) of [4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]acetic acid ethyl ester, 0.80 g (0.004 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, and 1.14 g (0.0082 mole) of potassium carbonate in 40 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 35% ethyl acetate-hexane to give 1.69 g (72% yield) of [4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:22][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:21])C(=O)OC(C)(C)C)[CH2:9][CH2:8]1.[Cl:33][C:34]1[C:35]2[CH:45]=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[ClH:33].[ClH:33].[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:22][C:4]=1[CH2:5][N:6]([CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][CH3:21])[CH2:9][CH2:8]1)[C:39]([C:38]1[S:37][C:36]2[CH:42]=[CH:43][CH:44]=[CH:45][C:35]=2[C:34]=1[Cl:33])=[O:40]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(-c2ccnc(C)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CNC1CCC(N(Cc2cc(-c3ccnc(C)c3)ccc2OC)C(=O)c2sc3ccccc3c2Cl)CC1
Product: Cl
Yield: 123.5 %

Procedure:
Biaryl amine 88 (250 mg, 0.57 mmol) is treated with 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (157 mg, 0.68 mmol) using Method D. The resultant amide (175 mg, 0.28 mmol) isolated after chromatography is then directly deprotected using Method F to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][C:3]=1[NH:19][NH2:20].O.[C:22]1([CH3:28])[CH:27]=[CH:26]C=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][C:3]=1[N:19]1[C:27]([CH3:26])=[C:22]([CH3:28])[C:23]([CH3:24])=[N:20]1
Reactant: Cc1ccccc1
Reactant: NNc1cc(OS(=O)(=O)c2ccccc2)c(Cl)cc1F
Solvent: O
Product: Cc1nn(-c2cc(OS(=O)(=O)c3ccccc3)c(Cl)cc2F)c(C)c1C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of (2-fluoro-4-chloro-5-phenylsulfonyloxyphenyl)-hydrazine (31.7 g), 3-methylpenta-2,4-dione (11.4 g) and water (150 ml) was stirred at 70° C. for one hour. After the reaction mixture was cooled, toluene was added thereto whereby to form two layers. The toluene layer thus separated was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent by distillation in vacuo gave the titled compound (37.5 g) as a pale brown crystalline solid. Recrystallization of this solid from carbon tetrachloride afforded a white crystalline solid. nD23 =1.5492.
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(CC)CC)C.[CH2:27]=[C:28]=[O:29]>C(Cl)Cl>[C:28]([O:9][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:29])[CH3:27]
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: C=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1

Procedure:
A solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (13 mg, 0.05 mmol) in anhydrous CH2Cl2 (1 ml) is cooled in an ice-bath and treated with triethylamine (Et3N) (7 μl, 0.05 mmol). Ketene is passed through the resulting solution for 10 mins. The solvent and excess ketene are removed in vacuo to leave crude benzyl 3-acetoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.ClC[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.[C:32]1(C)C=CC=CC=1>O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:32][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:22]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2
Reactant: Cc1ccccc1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: ClCc1ccnc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2c(C)nc(O)c(Cc3cnc4ccccc4c3)c2cc1OC
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (120 mg, 547 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.58 mL, 1.16 mmol) at RT followed by MDE 32016 (130 mg, 607 μmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) gave 37 mg of 6,7-dimethoxy-1-methyl-4-(quinolin-3-ylmethyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (4 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-(quinolin-4-ylmethyl)isoquinolin-3-ol dihydrochloride 25 as a brown solid (44 mg, 19% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1)CCC>>[C:8]1([C:4]2[N:3]=[C:2]([C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:30])[F:31])=[N:27][C:22]4=[N:21][CH:20]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1cccc(-c2ccccc2)n1
Product: FC(F)(F)c1ccn2c(-c3cccc(-c4ccccc4)n3)cnc2n1
Yield: 34.4 %

Procedure:
2-Bromo-6-phenylpyridine (0.17 g, 0.7 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.9 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with dichloromethane on a gradient of methanol (0-10%) and trituration with ethyl acetate gave 3-(6-phenylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (82 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 7.39 (1H, d, J 7), 7.53 (3H, m), 7.70 (1H, d, J 8), 7.78 (1H, d, J 8), 7.91 (1H, dd, J 8 and 8), 8.01 (2H, d, J 8), 8.53 (1H, s), 10.62 (1H, d, J 7); m/z (ES+) 341 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29].[NH2:31][C@H:32]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:33][C:34]([O:36]C(C)(C)C)=[O:35]>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:31][C@H:32]([C:41]([CH3:42])([CH3:43])[CH3:44])[CH2:33][C:34]([OH:36])=[O:35])=[O:15])[CH:11]=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(C)(C)C
Product: Cc1ccccc1-c1ccc(C(=O)N[C@@H](CC(=O)O)C(C)(C)C)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Product: Cl
Yield: 132.5 %

Procedure:
According to the process described in Example 2.2, the peptide coupling performed between 425 mg (1 mmol) of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylic acid (Example 4.2) and 206 mg (2.05 mmol) of tert-butyl(3S)-3-amino-4,4-dimethylpentanoate (J. Org. Chem., 1999, 64, 6411-6417) gives 390 mg of (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoic acid hydrochloride in the form of a white powder.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH:20]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CCCCCc1ccccc1
Reactant: CCCCc1ccccc1
Product: Cc1cccc2ccccc12
Product: c1ccc2ccccc2c1
Temperature: 550 °C

Procedure:
Cyclodehydrogenation was carried out in the same way as Example 1 except that n-amylbenzene (a reagent produced by Tokyo Kasei K.K., purity: 98.9%) was used in place of n-butylbenzene, and that it was gasified in a nitrogen stream and introduced into the catalyst layer maintained at 550° C., at LHSV of 0.085. The conversion ratio of n-amylbenzene was 95.5%. Also, 1-methylnaphthalene was obtained at a selectivity of 72.1%, while naphthalene was obtained at a selectivity of 11.4%.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C1(C[N:15]2[CH2:24][CH2:23][C:18]3([S:22][CH2:21][CH2:20][S:19]3)[CH2:17][CH2:16]2)C=CC=CC=1.[OH-].[Na+]>ClC(Cl)C>[ClH:1].[S:19]1[C:18]2([CH2:23][CH2:24][NH:15][CH2:16][CH2:17]2)[S:22][CH2:21][CH2:20]1
Reactant: c1ccc(CN2CCC3(CC2)SCCS3)cc1
Reactant: CC(Cl)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: C1CC2(CCN1)SCCS2
Product: Cl
Temperature: 25 °C
Yield: 78.1 %

Procedure:
0.74 ml (0.007 mol) of 1-chloroethyl chloroformate is added to a solution of 1.6 g (0.006 mol) of 8-(phenylmethyl)-1,4-dithia-8-azaspiro-[4.5]decane in 20 ml of dichloroethane; the mixture is heated under reflux for 1.5 h, it is cooled to room temperature, 8 ml of 1 M sodium hydroxide are added, the organic phase is decanted off, the aqueous phase is washed with 25 ml of dichloromethane, the organic phases are dried with sodium sulphate and then evaporated to dryness; the residue is dissolved in 35 ml of methanol and the solution is heated at 60° C. for 40 min; the solvent is evaporated off and the solid obtained is triturated with diisopropyl ether; 0.993 g of 1,4-dithia-8-azaspiro[4.5]decane hydrochloride is thus obtained in the form of a white solid. Yield 78%. Melting point >250° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([N:13]([CH3:40])[C@H:14]([C:18]([N:20]([CH3:39])[C@H:21]([C:34]([NH:36][O:37][CH3:38])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:11]([N:13]([CH3:40])[C@H:14]([C:18]([N:20]([CH3:39])[C@H:21]([C:34]([NH:36][O:37][CH3:38])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:31])[CH3:32])[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1
Reactant: CONC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CONC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](N)Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To a solution of Boc-Phe(4-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NHOMe (972 mg, 1.508 mmol) in methylene chloride (10 ml), TFA (7 ml) was added and stirred for 30 min. The mixture was concentrated under reduced pressure and the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=20:1), giving the titled compound (288 mg, 34%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH3:17][N:18]([CH3:25])[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:17][N:18]([CH3:25])[CH:19]1[CH2:24][CH2:23][N:22]([C:7](=[O:9])[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:21][CH2:20]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(O)C(=O)c1cccs1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C1CCN(C(=O)C(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
2-Thiopheneglyoxylic acid (300 mg, 1.9 mmol) was dissolved in 10 mL of methylene chloride. A 2.0 M solution of oxalyl chloride in methylene chloride (1.1 mL, 2.1 mmol) was then added, followed by 10 μL of DMF. The resulting solution was stirred at room temperature for 1 hour, then a solution of dimethylpiperidin-4-ylamine (271 mg, 2.1 mmol) and DIPEA (1.0 mL, 5.8 mmol) in 2 mL of methylene chloride was added. 4-Dimethylaminopyridine (12 mg, 96 μmol) was then added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was then extracted with a saturated sodium bicarbonate solution, and the organic layer was dried over Na2SO4 and concentrated to yield the crude intermediate (4a) (498 mg), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH2:9][CH3:10])[CH:7]=1.O.[NH2:14][NH2:15].O>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:15][N:14]=[C:8]2[CH2:9][CH3:10]
Reactant: CCC(=O)c1cc(Br)ccc1F
Reactant: NN
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1n[nH]c2ccc(Br)cc12

Procedure:
A solution of 7.50 g (32.5 mmol) 1-(5-bromo-2-fluorophenyl)-1-propanone (Example 6A) in 1-methyl-2-pyrrolidinone (NMP; 100 ml) was treated with 3.25 g (3.16 ml, 64.9 mmol) hydrazine hydrate and stirred at reflux temperature for 16 h. Upon cooling, the mixture was poured into a mixture of ice and water. The precipitate was collected by filtration and washed thoroughly with water to yield 4.56 g (62% of th.) of the title compound as a beige-coloured solid.
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]2[CH:11]=[C:12]([C:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=3)[S:13][C:6]=12.[NH4+].[Cl-].O>CCO.[Fe]>[F:1][C:2]1[CH:24]=[C:23]([CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=3)[S:13][C:6]=12)[NH2:25]
Reactant: CN1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reaction time: 0.67 h
Yield: 66.7 %

Procedure:
To a mixture of 4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine 259 (279 mg, 0.72 mmol) and NH4Cl (33 mg, 0.612 mmol) in EtOH (7.2 mL)/water (3.6 mL) at 100° C. Fe (342 mg, 6.2 mmol) was added in one portion and the mixture heated to reflux with vigorous stirring for 40 min. The mixture was filtered through Celite®, the Celite® washed with EtOH and the combined organic solutions concentrated under reduced pressure. The residue was dissolved in MeOH and purified by flash chromatography (DCM/MeOH 5:1) giving 260 (171.3 mg, 0.48 mmol, 67% yield) as a yellow solid. MS (m/z): (M+1) 356.0 (100%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].[Br:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=CC=1N.[CH3:22][C:23]1([CH3:36])[O:28][C@@H:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H](N)C[O:24]1>CN(C)C1C=CN=CC=1.CN(C)C=O>[Br:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:11][C:12]=1[NH:8][C:1]([NH:3][C@H:7]1[CH2:6][O:24][C:23]([CH3:22])([CH3:36])[O:28][C@H:27]1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:2]
Reactant: CC1(C)OC[C@H](N)[C@H](c2ccccc2)O1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(N)c(Br)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)N[C@H]2COC(C)(C)O[C@H]2c2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.8 %

Procedure:
To a stirred solution of 285 mg (1.76 mmol) of 1,1′-carbonyldiimidazole and 5 mg (0.041 mmol) of 4-(dimethylamino)pyridine in N,N-dimethylformamide (3.0 mL) was added 0.22 mL (1.76 mmol) of 2-bromo-4-methylaniline. After stirring for 15 min at 25° C., the reaction was heated to 50° C. At 50° C., a solution of 184 mg (0.88 mmol) of (4S,5S)-amine 1 in N,N-dimethylformamide (1 mL) was added dropwise. The reaction was heated to 100° C. for 4 h and then cooled to 25° C. and partially concentrated under reduced pressure. The mixture was taken up in approximately 100 mL of dichloromethane and washed with water. The organic layers were concentrated to a cream-colored solid that was purified by column chromatography (dichloromethane/ethyl acetate/hexane) to yield 73 mg (20%) of the title compound as a white foam.