Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].N1C=CC=CC=1.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+].[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[NH2:34]>C(OCC)(=O)C.O.CCOCC>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](=[O:9])[NH:34][C:30]1[S:29][CH:33]=[CH:32][N:31]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: Nc1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(=O)Oc1ccccc1C(=O)Nc1nccs1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 51.9 %

Procedure:
2-(Acetyloxy)-benzoic acid (500, 1.80 g, 10.0 mmol) was placed in a 250 mL round bottom flask equipped with a stirbar, vacuum adapter and septum. Ether (100 mL) and pyridine (1.00 mL, 12.4 mmol) were added to create a clear, colorless solution, which was cooled to zero in an ice bath before thionyl chloride (875 μL, 12.0 mmol) was added dropwise over ca. 30 sec. A thick white precipitate formed upon the addition of each drop. The reaction mixture was stirred for 90 minutes at 0° C. before being filtered through paper, and removing the solvents in vacuo. Sodium bicarbonate (3.42 g, 40.7 mmol) and 1,3-thiazol-2-amine (1.00 g, 10.0 mmol) were weighed into a 250 mL round bottom flask and water (30 mL) and ethyl acetate (30 mL) were added to form a colorless biphase, which was stirred rapidly. The crude acid chloride was suspended in ethyl acetate (10 mL) and added dropwise to the rapidly stirring biphase. The resulting biphase was capped lightly and stirred rapidly at room temperature for 2 hours. The biphase layers were separated, and the aqueous was extracted twice with ethyl acetate. The combined organics were washed with brine, dried with MgSO4, filtered, and concentrated to give 501 (1.36 g, 52%) as a colorless powder, which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][O:22][NH:23][CH3:24]>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:23]([O:22][CH3:21])[CH3:24])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Product: CON(C)C(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Yield: 95.6 %

Procedure:
The product from Example 126c (1.0 g, 3.20 mmol) was reacted with N-methoxymethanamine (391 mg, 6.41 mmol) for 12 h following the procedure from Example 126d giving the title compound (1.03 g, 100%).
Reaction SMILES: [C:1]([CH2:4][C:5]1([C:14]([OH:16])=[O:15])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([OH:3])=O>C(Cl)(=O)C>[CH2:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]21[CH2:4][C:1](=[O:3])[O:16][C:14]2=[O:15]
Reactant: O=C(O)CC1(C(=O)O)Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: O=C1CC2(Cc3ccccc3C2)C(=O)O1

Procedure:
A solution of 2-(carboxymethyl)indane-2-carboxylic acid from Step C (1.10 g, 4.99 mmol) in acetyl chloride (18 mL) was heated at reflux for 18 h, then concentrated in vacuo. The residue was recrystallized from toluene to give 1′,3′-dihydrospiro[furan-3,2′-indene]-2,5(4H)-dione as an ivory solid. This solid was dissolved in CH2Cl2 (25 mL) and NH3 (g) was bubbled into the mixture for 20 min. After a further 30 min, the solvent was evaporated under reduced pressure. The resulting solid was dried under high vacuum for 1 h, then resuspended in acetyl chloride (20 mL) and heated to reflux for 18 h. The solvent was removed in vacuo and the crude solid was recrystallized from EtOH:Et2O to afford the title compound. MS: m/z=202 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CC(C)COC(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: CC(C)COC(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using isobutyl chloroformate (72 μL, 0.55 mmol) to provide isobutyl [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]carbamate (0.046 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][P:15]([C:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])[CH3:21])([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O.CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][P:15]([C:20]([O:22][CH2:23][CH3:24])([O:25][CH2:26][CH3:27])[CH3:21])([O:17][CH2:18][CH3:19])=[O:16])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)(OCC)P(=O)(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(C)(OCC)P(=O)(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)OCC
Temperature: 25 °C

Procedure:
Adapting a literature known protocol (Dayal, et al., Steroids, 1990, 55(5), 233-237), a reaction mixture of methyl(2R)-2-(tert-butoxycarbonylamino)-3-(1,1-diethoxyethyl(ethoxy)-phosphoryl)propanoate (10a) (4.11 g, 10.0 mmol) and commercial lithium hydroxide monohydrate (LiOH.H2O) (839 mg, 20.0 mmol) in a mixture of water (20 mL) and methanol (MeOH) (5 mL) is stirred at room temperature. The reaction is monitored by TLC and/or LC/MS to completion. Acidic aqueous work-up and purification by silica gel column chromatography furnish the title compound (2R)-2-(tert-butoxycarbonylamino)-3-(1,1-diethoxyethyl(ethoxy)phosphoryl)propanoic acid (10b) which may be used directly in the next step without further isolation and purification.
Reaction SMILES: CN(C)CCN(C)C.[C:9]([O-:12])([O-])=[O:10].[K+].[K+].[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[CH:16]>Cl[Cu]>[C:17]1([C:15]#[C:16][C:9]([OH:12])=[O:10])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl[Cu]
Agent: CN(C)CCN(C)C
Agent: [K+]
Product: O=C(O)C#Cc1ccccc1

Procedure:
An initial experiment was conducted by using 2 mol % of CuCl, 2 mol % of TMEDA (N,N,N′,N′-tetramethylethylenediamine) ligand, and K2CO3 as base for the carboxylation of 1-ethynylbenzene at ambient temperature and atmospheric pressure. Remarkably, phenylpropiolic acid was produced in excellent yield after acid workup. The isolated pure product was characterized by NMR and elemental analysis. Phenylpropiolic acid was further converted into its methylester and characterized by NMR and GC/MS.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].N1C=CC=CC=1.[Br:20][CH2:21][C:22](Br)=[O:23]>CCOCC>[Br:20][CH2:21][C:22]([C:4]([N:3]([CH2:1][CH3:2])[CH2:12][CH3:13])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:23]
Reactant: CCN(C=Cc1ccccc1)CC
Reactant: O=C(Br)CBr
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCN(CC)C(=Cc1ccccc1)C(=O)CBr
Temperature: 5 °C

Procedure:
To a solution of 17.5 g. of diethylstyrylamine in 200 ml. of ether was added 8.5 g. of pyridine. The mixture was cooled to 5° C. and a solution of 20.1 g. of bromoacetyl bromide in 200 ml. of ether was added over a period of about 4 hours. The mixture was filtered and the residue on the filter was washed with 300 ml. of ether. The combined ether filtrate and washings was washed with 1 N hydrochloric acid, 0.1 N sodium hydroxide, saturated aqueous sodium chloride, and dried over magnesium sulfate and activated carbon. The mixture was filtered and the ether was evaporated to give a quantitative yield of α-bromoacetyl-β-diethylaminostyrene. The product was shown by NMR spectrum to be a mixture of the cis and trans isomers.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[NH2:15][CH2:16][C:17]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23]2[C:18]=1[N:19]=[C:20]([O:32][CH3:33])[C:21]([O:30][CH3:31])=[N:22]2>COC(C)(C)C.ClCCl>[CH3:31][O:30][C:21]1[C:20]([O:32][CH3:33])=[N:19][C:18]2[C:23](=[CH:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][C:17]=2[CH2:16][NH:15][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH3:8])[N:22]=1
Reactant: CCCCC(=O)Cl
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN)c2nc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CCCCC(=O)NCc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
79 μl (0.567 mmol) of triethylamine and 55 μl (0.454 mmol) of n-valeroyl chloride are added to a suspension of 100 mg (0.378 mmol) of 5-aminomethyl-2,3-dimethoxy-7-nitro-quinoxaline in 2 ml of tert-butyl methyl ether and the mixture is stirred at room temperature for 16 hours. The mixture is then taken up in dichloromethane, washed with 1 N hydrochloric acid and with 1 N sodium hydroxide solution, dried over sodium sulfate and concentrated by evaporation. The title compound is obtained in the form of a yellowish powder.
Reaction SMILES: [Li+].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]([O-:23])=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([CH3:5])[CH3:4].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:58]([C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH:68]2[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]2)=[CH:63][C:62]=1[C:74]([F:77])([F:76])[F:75])([O-:60])=[O:59]>CN(C)C=O.ClCCl.O1CCCC1>[CH2:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]([N:71]3[CH2:72][CH2:73][CH:68]([NH:67][C:64]4[CH:65]=[CH:66][C:61]([N+:58]([O-:60])=[O:59])=[C:62]([C:74]([F:75])([F:76])[F:77])[CH:63]=4)[CH2:69][CH2:70]3)=[O:23])[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)COc1ccc(N2CCN(CCC(=O)[O-])CC2)cc1
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)COc1ccc(N2CCN(CCC(=O)N3CCC(Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1
Reaction time: 0.08 h

Procedure:
3-[4-(4-Isobutoxy-phenyl)-piperazin-1-yl]-propionic acid lithium salt (35 mg; 0.11 mmol, prepared in accordance with Example 25), diisopropylethyl amine (50 μL; 0.10 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (38 mg; 0.10 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (33 mg; 0.10 mmol, prepared in accordance with Example 8) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 3 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (30 mg; 0.05 mmol). The structure was confirmed using Protocol II-A. Calculated mass=578; observed mass=578; HPLC retention time=3.54 min.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:3]=1.Cl[C:16]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[F:25][C:23]1[C:22]([F:26])=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([NH:7][C:5]2[N:4]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=3)[N:3]=[C:2]([CH3:1])[CH:6]=2)[CH:24]=1
Reactant: Cc1cccc(-n2nc(C)cc2N)n1
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-n2nc(C)cc2Nc2cc(F)c(F)cc2C(=O)O)n1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of 3-methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazol-5-ylamine (5.65 g, 30.0 mmol), 2-chloro-4,5-difluorobenzoic acid (6.93 g, 36.0 mmol), copper acetate (II) (0.545 g, 3.00 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in N,N-dimethylformamide (30 mL) was heated under reflux under an argon atmosphere for 2 hours. The solution was allowed to cool to room temperature, and the reaction mixture was poured into water. The solution was made weakly acidic by the addition of 1N hydrochloric acid, and the resulting crude crystals were collected by filtration. The crystals were washed with water and air dried to give crude 4,5-difluoro-2-[[3-methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (8.18 g, 79% yield). A solution of the compound (7.00 g, 20.3 mmol) in phosphorus oxychloride (9.73 mL, 104 mmol) was heated under reflux for 30 minutes. The reaction solution was allowed to cool to room temperature, and the residue was poured into iced water. The solution was neutralized by the addition of a sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform) to give crude 4-chloro-6,7-difluoro-3-methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (2.70 g, 39% yield). To a solution of the compound (2.70 g, 36.0 mmol) in ethanol (120 mL), 6N hydrochloric acid (4 mL, 24.0 mmol) was added, and the mixture was heated under reflux for 3 hours. The reaction solution was allowed to cool to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol, air dried and recrystallized from ethanol to give the title compound (1.68 g, 66% yield).
Reaction SMILES: C1(S(CC2C(C(O)=O)=C(NCCNC(OC(C)(C)C)=O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.[C:36]1([S:42]([CH2:45][C:46]2[C:51]([C:52]([O:54]C)=[O:53])=[C:50]([O:56][CH3:57])[C:49]([Br:58])=[CH:48][CH:47]=2)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:36]1([S:42]([CH2:45][C:46]2[C:51]([C:52]([OH:54])=[O:53])=[C:50]([O:56][CH3:57])[C:49]([Br:58])=[CH:48][CH:47]=2)(=[O:44])=[O:43])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: CC(C)(C)OC(=O)NCCNc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Product: COc1c(Br)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 121, starting from methyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 65).
Reaction SMILES: Br[C:2]1[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=1)=[N:6][N:5]([CH3:11])[CH:4]=2.[CH2:12]([OH:15])[C:13]#[CH:14]>C(N(CC)CC)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>[CH3:11][N:5]1[CH:4]=[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=[C:2]2[C:14]#[C:13][CH2:12][OH:15])=[N:6]1
Reactant: C#CCO
Reactant: Cn1cc2c(Br)cccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cn1cc2c(C#CCO)cccc2n1
Temperature: 70 °C
Reaction time: 14 h
Yield: 45.7 %

Procedure:
Under argon gas atmosphere, a mixture of 4-bromo-2-methyl-2H-indazole (1.00 g, 4.74 mmol), propargyl alcohol (1.10 mL, 18.9 mmol) and bis(triphenylphosphine)palladium(II) dichloride (665 mg, 0.947 mmol) in triethylamine (47 mL) was stirred at 70° C. for 14 hr, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and insoluble material was filtered off. The filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=70/30→100/0) and the obtained crudely purified product was washed with ethyl acetate to give the title compound (403 mg, yield 46%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[Cl:17].[CH3:18][C:19]1[N:24]=[C:23]([SH:25])[N:22]=[C:21]([OH:26])[CH:20]=1.C(N(CC)CC)C>C(O)C>[Cl:17][C:4]1[CH:5]=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[CH2:11][CH2:10]2)[CH:7]=[CH:8][C:3]=1[CH2:2][S:25][C:23]1[N:22]=[C:21]([OH:26])[CH:20]=[C:19]([CH3:18])[N:24]=1
Reactant: CCN1CCN(c2ccc(CBr)c(Cl)c2)CC1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN1CCN(c2ccc(CSc3nc(C)cc(O)n3)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[4-(bromomethyl)-3-chlorophenyl]-4-ethylpiperazine, 6-methyl-2-sulfanylpyrimidin-4-ol (1.42 g, 10 mmol) and triethylamine (2.8 mL, 20 mmol) were mixed in ethanol (50 mL). The mixture was stirred at room temperature for 2 hours. After evaporation, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide crude product, which was further purified by CombiFlash to yield a white solid (400 mg, 5% overall yield); 1H NMR (400 MHz, DMSO-d6): δ 1.16 (t, 3H), 2.20 (s, 3H), 2.48 (q, 4H), 3.06 (q, 4H), 4.35 (s, 2H), 5.98 (br, 1H), 6.88 (d, 1H), 7.00 (s, 1H), 7.42 (d, 1H); M+379.
Reaction SMILES: [S:1]1(=[O:10])(=[O:9])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3][CH2:2]1.C([Li])CCC.[C:16](=[O:18])=[O:17]>C1COCC1.CCCCCC.CCOCC>[S:1]1(=[O:10])(=[O:9])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3][CH:2]1[C:16]([OH:18])=[O:17]
Reactant: O=S1(=O)CCc2ccsc21
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)C1Cc2ccsc2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
2,3-Dihydrothieno[2,3-b]thiophene-1,1-dioxide (35.5 g, 0.204 mol) in THF (300 mL) was cooled to -78° C. under a nitrogen atmosphere. A solution of n-butyllithium in hexane (82.7 mL, 2.47M) was added dropwise over a period of 1 hour. The dark red solution was stirred for an additional 15 minutes and poured over dry ice (2 L) in ether (2 L). The reaction was allowed to warm to room temperature and the product partitioned between aqueous sodium hydroxide and ether. The aqueous phase was extracted twice with ethyl acetate, then rendered acidic (pH 1) with concentrated HCl. The resulting yellow suspension was extracted into ethyl acetate. The ethyl acetate solution was washed with saturated brine and dried over magnesium sulfate, filtered, and the solvent removed in vacuo to provide an 8:2 mixture of carboxylic acids. The solid was triturated with 5% acetonitrile in ether and collected by filtration. This was repeated a total of four times to remove most of the undesired minor product. The filtrates from the washings were combined to give approximately 1:1 mixture of carboxylic acids (17.6 g, 39%), which could be separated by column chromatography on silica gel with 10% acetic acid in chloroform. The filtered product was a light tan powder which was dried in a vacuum oven at 20° C. under house vacuum overnight to provide the title compound (21.3 g, 47%) in >95% purity.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([NH:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:7]([O:6][N:5]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:3]([N:2]([CH3:14])[CH3:1])=[O:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)C(=O)NOCc1ccccc1
Reactant: CCCCCCCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCN(OCc1ccccc1)C(=O)N(C)C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
To a solution of this urea (1.59 g, 8.19 mmol) in DMF (13 ml) at 50° C. under nitrogen was added sodium hydride (360 mg of a 60% dispersion in oil). The resulting solution was stirred for 45 minutes, and 1-bromooctane (1.83 ml) was added. After 16 hours, the mixture was poured into 1% aqueous citric acid (75 ml) and extracted 3 times with 1:1 hexane-ether. The combined extracts were dried (MgSO4), filtered, and evaporated. Purification by chromatography on silica provided N-benzyloxy-N-octyl-N',N'-dimethylurea as a colorless oil (2.04 g, 81% yield). Hydrogenolysis as in Example 2 above, and recrystallization from hexane at -40° C., provided the title compound as a white solid (875 mg, 57% yield), mp 29°-30° C.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[C-:12]#[N:13].[Na+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:12]#[N:13])=[O:8]
Reactant: [C-]#N
Reactant: Cc1ccccc1C(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1C(=O)C#N
Reaction time: 2 h

Procedure:
To a stirred solution of o-toluoyl chloride (38.86 g) in dichloromethane (250 ml) at room temperature was added water (20.0 ml) followed immediately by tetrabutylammonium bromide (0.15 g) and sodium cyanide (13.0 g). The reaction mixture was stirred vigorously for 11/2 hours, then filtered. The filtrate was washed with water (2×100 ml) then dried (MgSO4) and evaporated under reduced pressure to give a golden oil. Distillation under vacuum gave 2-methylbenzoyl cyanide, as a colourless oil, bp 47°-50°/0.05 mm. To 85% w/w sulphuric acid (140 ml) at room temperature was added sodium bromide (20 g) followed immediately by the dropwise addition of 2-methylbenzoyl cyanide (34.8 g). The reaction mixture was then heated gently until the exothermic reaction started and then maintained at 70° C. for 10 minutes by cooling. Methanol (400 ml) was added and the mixture heated under reflux for 1 hour, cooled and diluted with ice/water (500 ml). Extraction with diethyl ether gave a golden oil which was distilled under vacuum to give methyl oxo(o-tolyl)acetate, as B colourless oil, bp 75°-85°/0.4 mm.
Reaction SMILES: COC1C=CC(C)=CC=1S(C1C=C(C(OC)=O)C2OC=CC=2C=1)(=O)=O.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([C:36]2[CH:37]=[C:38]([C:45]([O:47][CH3:48])=[O:46])[C:39]3[O:43][CH2:42][CH2:41][C:40]=3[CH:44]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([C:36]2[CH:37]=[C:38]([C:45]([O:47][CH3:48])=[O:46])[C:39]3[O:43][CH:42]=[CH:41][C:40]=3[CH:44]=2)(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: COC(=O)c1cc(S(=O)(=O)c2ccc(C)cc2)cc2c1OCC2
Agent: COC(=O)c1cc(S(=O)(=O)c2cc(C)ccc2OC)cc2ccoc12
Product: COC(=O)c1cc(S(=O)(=O)c2ccc(C)cc2)cc2ccoc12

Procedure:
The title compound was prepared according to the procedure of Intermediate 67 starting from methyl 5-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1-benzofuran-7-carboxylate (117 mg, 0.4 mmol; obtained in Step 1). Yield: 62 mg (53%) after purification by preparative HPLC (System F; 40-60% MeCN). MS (ESI+) for C17H16O5S m/z 331 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:23].[Na+].O.[OH-].[Na+]>O.CO>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([S:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:23])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CSC2CCN(Cc3ccccc3)CC2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=S(Cc1ccccc1)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
0.37 g (0.00124 mol) of 1-benzyl-4-benzylsulfanyl-piperidine was suspended in a mixture of 20 ml of water/methanol (1:1) and treated with 2.66 g (0.0124 mol) of sodium periodate. The mixture was stirred at room temperature for 3 hrs., 150 ml of water were added, the pH was adjusted to 8-9 with 1N aqueous NaOH, the mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the residue was chromatographed on silica gel with methanol/dichloro-methane (1:19). The fraction having Rf 0.31 was the desired product. 0.17 g (44%) of (RS)-1-benzyl-4-benzylsulfinyl-piperidine was obtained as white crystals; m.p. 123°-125`0.