Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].[CH:27]1([S:34][CH2:35][CH2:36]Cl)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[O:1]=[C:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:36][CH2:35][S:34][CH:27]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: ClCCSC1CCCCCC1
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H]1CN(CCSC2CCCCCC2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 72 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
A mixture composed of 3.06 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate, 1.79 g of 2-chloroethyl cycloheptyl sulfide, 5.39 g of potassium carbonate, and 1.29 g of potassium iodide in 75 cm3 of acetonitrile was heated with stirring and under an inert atmosphere at a temperature in the region of 72° C. for 24 hours. After cooling to approximately 20° C., the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μ; diameter 4 cm; mass 150 g), elution was carried out with an ethyl acetate/methanol (95/5 by volume) mixture, and 50-cm3 fractions were collected. The fractions comprising the desired product were combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 2.6 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cycloheptylthio)ethyl]piperidine-3-carboxylate were obtained in the form of a viscous oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[CH:10]=1)=[S:7].ClC(Cl)(Cl)Cl.BrBr>C(#N)C>[CH2:15]([C:11]1[CH:12]=[CH:13][C:14]2[S:7][C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])=[N:8][C:9]=2[CH:10]=1)[CH2:16][CH3:17]
Reactant: CCCc1cccc(NC(=S)NCCCO)c1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CCCc1ccc2sc(NCCCO)nc2c1

Procedure:
To a stirred mixture of 27.7 parts of N-(3-hydroxypropyl)-N'-(3-propylphenyl)thiourea and 240 parts of tetrachloromethane are added 17.6 parts of bromine and the whole is stirred and refluxed for 1 hours. About 80 parts of acetonitrile are added and the formed hydrobromide salt is allowed to crystallize. It is filtered off, washed with acetonitrile and dissolved in water. The free base is liberated in the conventional manner with ammonium hydroxide and extracted with 1,1'-oxybisethane. The extract is dried, filtered and evaporated, yielding 18 parts of 3-(5-propyl-2-benzothiazolylamino)-1-propanol as an oily residue.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[Si:9]([O:16][CH2:17][CH2:18][CH2:19]O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Si:9]([O:16][CH2:17][CH2:18][CH2:19][N:4]1[C:5](=[O:6])[CH2:7][CH2:8][NH:1][C:2]1=[O:3])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:11])[CH3:10]
Reactant: O=C1CCNC(=O)N1
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCN1C(=O)CCNC1=O

Procedure:
A mixture 5,6-dihydrouracil (4.45 g, 39.028 mmol), 3-{[tert-butyl(dimethyl)silyl]oxy}propan-1-ol (3 mL, 13.01 mmol) and Cs2CO3 (16.95 g, 52.04 mmol) in dry DMF (120 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. Combined organic extracts were washed with water and brine, dried over Na2SO4 and the solvent evaporated in vacuo. Purified by chromatography on silica gel using ethyl acetate and hexane (60:40) to give the title compound.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.S(=O)(=O)(O)O.[C:17]([OH:30])(=[O:29])/[CH:18]=[CH:19]/[C:20]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:22]([OH:23])[CH:21]=1.[C:31]1([CH:38]=[CH:37][CH:36]=[C:34](O)[CH:33]=1)[OH:32]>O1CCOCC1>[OH:32][C:31]1[CH:38]=[C:37]2[C:36]([C@@H:19]([C:20]3[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:22]([OH:23])[CH:21]=3)[CH2:18][C:17](=[O:30])[O:29]2)=[CH:34][CH:33]=1
Reactant: COc1ccc(/C=C/C(=O)O)cc1O
Reactant: Oc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: COc1ccc([C@H]2CC(=O)Oc3cc(O)ccc32)cc1O

Procedure:
0.5 g para-toluenesulfonic acid and 1.5 ml concentrated sulfuric acid were added to a mixture of 50 mmol isoferulic acid and 75 mmol resorcinol in 75 ml of 1,4-dioxane and heated under reflux for 14 hours. As the reaction was not completed at this time point according to LC-MS, a further 1.5 ml of concentrated sulfuric acid was added and the mixture was heated for a further 10 hours. Then a large part of the solvent was removed in a rotary evaporator and the product mixture was taken up in 200 ml ethyl acetate. The organic phase was washed twice with 50 ml demineralized water and 5% sodium bicarbonate solution each time and once with saturated sodium chloride solution. The organic phase was then dried over sodium sulfate and after removing the solvent, the product was purified by silica-gel column chromatography (solvent: ethyl acetate/hexane 4:5), recrystallized from a solvent mixture of diethyl ether/pentane (1:6) and the resultant product was dried at 60° C. in a vacuum drying cabinet.
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:29][CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[ClH:29].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: ClCCN1CCCC1
Agent: Cl
Product: O=C1N(CCN2CCCC2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 179° C. and MS: m/e=467.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 1-(2-chloroethyl)-pyrrolidine.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])C.C(=O)([O-])O.[Na+]>C(O)=O>[CH2:1]([N:8]([CH:23]=[O:25])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: O=CN(Cc1ccccc1)C1CCCc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of N-benzyl-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (2.8 g), formic acid (8 ml) and acetic anhydride (16 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and extracted twice with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated in vacuo to give N-benzyl-N-formyl-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (2.71 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:10])[F:9])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:9][CH:8]([F:10])[C:4]1[CH:3]=[C:2]([C:16](=[O:18])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)c1cccc(C(F)F)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A mixture of 1-bromo-3-(difluoromethyl)benzene (0.72 g, 3.48 mmol), tributyl(1-ethoxyvinyl)tin (1.38 g, 3.83 mmol), dichlorobis(triphenylphosphine)-palladium(II) (0.24 g, 0.35 mmol) in toluene (12 mL) is heated at 100° C. under nitrogen atmosphere for 16 hours. After cooling to room temperature, 2M hydrochloric acid (12 mL) is added to the mixture. Then the resulting mixture is stirred at room temperature for 1 hour. The mixture is diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer is dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography on silica-gel eluting with n-hexane/ethyl acetate (30:1) to give 0.58 g (98% yield) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([S:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)Sc1ccc(OCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)Sc1ccc(OCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 2-[4-(1-methylpropylthio)phenoxy]ethanol (4.26 g, 20.0 mmol) and triethylamine (4.2 ml, 30.0 mmol) in 100 ml methylene chloride at 0° is added dropwise methanesulfonyl chloride (1.7 ml, 22.0 mmol). The mixture is stirred at 0° for 20 min, after which it is poured into ice water. The methylene chloride layer is washed with ice water, with cold 10% sulfuric acid, with cold 5% sodium bicarbonate and with cold brine, dried and the solvent removed to give 2-[4-(1-methylpropylthio)phenoxy]ethyl methanesulfonate.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH:2]([CH3:4])[CH3:3].C(N(C(C)C)C(C)C)C.Cl[C:27](=[O:49])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][O:38][C:39]2[CH:48]=[CH:47][CH:46]=[CH:45][C:40]=2[C:41]([O:43][CH3:44])=[O:42])=[CH:32][CH:31]=1>C(#N)C>[CH2:1]([N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=1)[C:27](=[O:49])[CH2:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][O:38][C:39]2[CH:48]=[CH:47][CH:46]=[CH:45][C:40]=2[C:41]([O:43][CH3:44])=[O:42])=[CH:34][CH:35]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)Cl)cc1
Reactant: CC(C)CNCc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)N(Cc2ccc(C(F)(F)F)cc2)CC(C)C)cc1
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
N-Isobutyl-N-[4-(trifluoromethyl)benzyl]amine (0.172 g, 0.746 mol) was dissolved in dry acetonitrile under N2 and N-ethyl-N,N-diisopropylamine (0.371 g, 2.867 mmol) was added. The mixture was stirred for 30 min and methyl 2-{2-[4-(2-chloro-2-oxoethoxy)phenyl]ethoxy}benzoate (0.200 g, 0.573 mmol) was added. The solution was stirred over night at room temperature. The crude was purified by flash chromatography (started with isocratic heptane/EtOAc 50/50 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation to give 0.242 g of methyl 2-{2-[4-(2-{isobutyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]ethoxy}benzoate (yield 77.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][CH:22]=[C:23]([CH2:26]Cl)[C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][SH:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][CH:22]=[C:23]([CH2:26][S:33][CH2:32][CH2:31][N:30]([CH3:34])[CH3:29])[C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1
Reactant: CN(C)CCS
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCSCc1csc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.4 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.70 g, 1.5 mmol) in DMF (5 mL) was added 2-(dimethylamino)ethanethiol (2.1 g, 15 mmol), followed by potassium carbonate (1.0 g, 7.2 mmol) and the reaction stirred at ambient temperature. After 24 hours, the mixture was poured into water (100 mL) and the resulting solid collected by filtration, washed with water and dried in vacuo. Purification by flash chromatography on silica gel afforded 0.28 g (35% yield) of N-(4-chlorophenyl)-2-[((3-chloro-4-(((2-(dimethylamino)ethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a cream-colored solid; NMR (DMSO-d6) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 3.7 (s, 2), 2.5 (t, 2), 2.4 (t, 2), 2.1 (s, 6) ppm.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20]([OH:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[C:17]([O:26][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:16]=1[CH3:44])(=O)C.Cl.[Cl:46][CH2:47][C:48]1[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[ClH:46].[CH3:23][O:22][C:19]1[C:18]([O:24][CH3:25])=[C:17]([OH:26])[C:16]([CH3:44])=[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[C:20]=1[O:21][CH2:47][C:48]1[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=1
Reactant: ClCc1ccncc1
Reactant: COc1c(O)c(CCCCCCCCCCOC(C)=O)c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(O)c(C)c(CCCCCCCCCCO)c(OCc2ccncc2)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
A mixture of 6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol (3.70 g) obtained in Example B-1, 4-chloromethylpyridine hydrochloride (1.96 g), potassium carbonate (5.00 g) and dimethylformamide (30 ml) was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (30 ml). Tetrabutylammonium fluoride trihydrate (1 g) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. Methanol (50 ml) and 1N sodium hydroxide solution (10 ml) were added to the residue, and the mixture was stirred at room temperature for 16 hours. After concentration, the residue was subjected to column chromatography on silica gel and eluted with ethyl acetate. The desired fraction was concentrated. The residue was dissolved in ethanol (30 ml), and conc. hydrochloric acid (0.7 ml) was added. The crystals obtained after concentration under reduced pressure were separated by filtration and washed with ether to obtain the desired compound (1.2 g).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:42][CH2:43][CH2:44][CH3:45])[N:19]([CH2:20][CH2:21][CH2:22][N:23]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][C:39]([OH:41])=[O:40])=[CH:34][CH:33]=3)[CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1.[CH3:46]O>>[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:42][CH2:43][CH2:44][CH3:45])[N:19]([CH2:20][CH2:21][CH2:22][N:23]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([CH2:38][C:39]([O:41][CH3:46])=[O:40])=[CH:36][CH:37]=3)[CH:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1ccc(CC(=O)O)cc1)C1CCN(C)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1ccc(CC(=O)OC)cc1)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Sulfuric acid (1 mL) was added to the product from step (i) (250 mg) in MeOH (10 mL). The mixture was stirred at rt for 15 h, then the solvent evaporated under reduced pressure. The residue was purified by RPHPLC to afford the title compound, yield 6.2 mg.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]12)=O)(C)(C)C.Cl>CO>[CH3:16][N:14]1[CH2:13][C@@H:10]2[C@@H:9]([NH:8][CH2:12][CH2:11]2)[CH2:15]1
Reactant: CN1C[C@H]2CCN(C(=O)OC(C)(C)C)[C@H]2C1
Agent: Cl
Solvent: CO
Product: CN1C[C@H]2CCN[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Example A6 (20.8 g, 0.86 mole) in MeOH (450 ml) was added aqueous 3N HCl (300 ml). The mixture was stirred at room temperature overnight, then concentrated to dryness at 30° C. under vacuum. The residue was treated with aqueous 1N NaOH to obtain a pH of 9-10. The mixture was concentrated to dryness. The crude material was purified by chromatography (eluting with a mixture of 10% MeOH and 1% NH4OH in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 4.12-4.17 (m, 1 H) 3.31-3.43 (m, 1 H) 3.19-3.30 (m, 1 H) 3.12 (d, J=11.53 Hz, 1 H) 2.88-3.01 (m, 1 H) 2.69 (dd, J=9.49, 2.37 Hz, 1 H) 2.40-2.52 (m, 2 H) 2.33 (s, 3 H) 2.12-2.28 (m, 1 H) 1.82-1.95 (m, 1 H). MS: (M+H)+=127.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[NH:7][C:8](=[O:27])[C:9]([I:26])=[C:10]([O:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=2)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CS(C)=O>[N:1]([C:6]1[NH:7][C:8](=[O:27])[C:9]([I:26])=[C:10]([O:17][C:18]2[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1c(Cl)[nH]c(=O)c(I)c1Oc1cc(C)cc(C)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(N=[N+]=[N-])[nH]c(=O)c(I)c1Oc1cc(C)cc(C)c1
Temperature: 50 °C
Yield: 69.2 %

Procedure:
Sodium azide (0.20 g, 3.12 mmol) was added to a solution of intermediate 3 (0.50 g, 1.56 mmol) in DMSO (5 ml), and the mixture was heated at 50° C. for 5 hours Reaction mixture was partitioned between water (30 ml) and ethyl acetate (40 ml). The organic layer was dried over magnesium sulfate and concentred. Flash chromatography (SiO2, CH2Cl2/ethanol 95:5) gave the desired product (0.49 g, 70%) as a white solid, m.p.=216–218° C.
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.[CH2:10]([NH:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[N:18]([CH3:23])[C:17]([CH3:25])([CH3:24])[CH2:16]1)[CH2:11][CH2:12][CH3:13]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:10]([N:14]([CH:15]1[CH2:16][C:17]([CH3:25])([CH3:24])[N:18]([CH3:23])[C:19]([CH3:21])([CH3:22])[CH2:20]1)[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNC1CC(C)(C)N(C)C(C)(C)C1
Reactant: CC1(C)COP(Cl)OC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCN(C1CC(C)(C)N(C)C(C)(C)C1)P1OCC(C)(C)CO1

Procedure:
18.4 g of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane are added dropwise, at room temperature, with stirring, to a solution of 19.7 g (0.1 mol) of 4-butylamino1,2,2,6,6-pentamethylpiperidine in 100 ml of triethylamine. After heating at the reflux temperature for 15 hours, the mixture is diluted with toluene and the precipitated hydrochloride is filtered off. Evaporation of the filtrate gives 2-[N-butyl(1,2,2,6,6-pentamethyl-4-piperidyl)amino]-5,5-dimethyl-1,3,2-dioxaphosphorinane as an oil which boils at 120° under 40 Pa (Compound No. 1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10]([CH2:14][C:15](OC)=[O:16])(=O)[CH2:11][CH3:12].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:11]([C:10]1[NH:1][C:2]2[C:7]([C:15](=[O:16])[CH:14]=1)=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH3:12]
Reactant: COc1ccc(N)cn1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCc1cc(=O)c2nc(OC)ccc2[nH]1
Yield: 39.3 %

Procedure:
A solution of 5-amino-2-methoxypyridine (50 g), methyl propionylacetate (57.3 g) and p-toluenesulphonic acid (0.5 g) in benzene (200 ml) was heated under reflux with azeotropic removal of water for 20 hours. Volatile material was removed by evaporation and the residue added to a refluxing eutectic mixure of 26.5% v/v diphenyl and 73.5% v/v diphenyl oxide (140 ml). The solution was heated under reflux for 1 hour, cooled and diluted with hexane (500 ml). The precipitated solid was filtered off and triturated with hot methanol (500 ml) to give 2-ethyl-6-methoxy-1,5-naphthyridin-4(1H)-one (E5) (32.3 g), as a pale brown solid, m.p. 279°-281° C.; NMR (d6 -DMSO): 1.2(t,3H), 2.65(q,2H), 3.95(s,3H), 6.3(br s, 1H), 7.15(d,1H), 7.95(d,1H).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2.[OH-].[Na+].C(OCC)(=O)C>FC(F)(F)C(O)=O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][CH2:16][NH:17]2
Reactant: COc1ccccc1-c1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cccc2c1CCN2
Temperature: -5 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
0.26 g of sodium cyanoborohydride is gradually added to a solution of 0.44 g of 4-(2-methoxyphenyl)indole in 5 ml of trifluoroacetic acid under argon, cooled to a temperature of about −5° C. The reaction mixture is stirred at a temperature of about −5° C. for 2 hours, and is then poured into 15 g of ice and alkalinized with 8 ml of a concentrated sodium hydroxide solution. After the addition of 30 ml of ethyl acetate, the mixture is stirred at ambient temperature for 1 hour, and then separated by settling out. The organic phase is separated and the aqueous phase is extracted with 15 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is treated again with a mixture of 15 ml of water, 15 ml of ethyl acetate and 3 ml of a concentrated sodium hydroxide solution and stirred at ambient temperature for 15 minutes, and then separated by settling out. The organic phase is separated and the aqueous phase is extracted with 2×15 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 25 g cartridge of 15-40 μm silica, elution being carried out with pure dichloromethane, at a flow rate of 30 ml/min. 0.14 g of 4-(2-methoxyphenyl)-2,3-dihydro-1H-indole is thus obtained in the form of an off-white solid, the characteristics of which are the following: