Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(Cl)(Cl)[Cl:21].[Cl:24][C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>O>[ClH:21].[CH3:10][N:11]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:25]([Cl:24])=[O:27]
Reactant: CNCCN1CCCCC1
Reactant: ClC(Cl)Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCN1CCCCC1)C(=O)Cl
Product: Cl
Reaction time: 1 h

Procedure:
With cooling with ice, N,N-diisopropylethylamine (10.6 mL) and N-methyl-2-piperidin-1-ylethanamine (7.10 g) were added in that order to chloroform (140 mL) solution of triphosgene (8.15 g). The reaction liquid was stirred for 1 hour with cooling with ice, and then water (25 mL) was added thereto. The reaction liquid was azeotroped with toluene and then dried overnight under reduced pressure to obtain methyl(2-piperidin-1-ylethyl)carbamyl chloride monohydrochloride (20.0 g) as a pale yellow oily substance. Not further purified, the compound was used in the next reaction. Chloroform (2.0 mL), N,N-diisopropylethylamine (0.342 mL), 7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one dihydrochloride (136 mg) were added to the obtained methyl(2-piperidin-1-ylethyl)carbamyl chloride monohydrochloride (100 mg), and stirred at 70° C. for 11 hours. The reaction liquid was concentrated under reduced pressure, and then purified through reversed-phase HPLC (0.1% TFA acetonitrile/H2O=5% to 50%, gradient) to obtain the entitled compound (57 mg, 24%) as a pale yellow oily substance.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH:23]4[C:28]([O:30]C)=[O:29])=[O:21])=[CH:14][C:13]=3[C:32]([F:35])([F:34])[F:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl[C:37]([O:39][CH3:40])=[O:38].N1C=CC=CC=1>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][N:25]([C:37]([O:39][CH3:40])=[O:38])[CH2:24][CH:23]4[C:28]([OH:30])=[O:29])=[O:21])=[CH:14][C:13]=3[C:32]([F:35])([F:33])[F:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CNCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)C(C(=O)O)C1

Procedure:
The title compound was prepared by treating the compound of Example 255 with methyl chloroformate and pyridine in CH2Cl2 at room temperature, and followed by hydrolysis under basic conditions (aq. NaOHlEtOH), producing a white solid, mp 102° C. (dec.). 1H NMR (DMSO-d6, 300 MHz) δ 62.85 (m, 1H), 3.02 (m, 1H), 3.20 (m, 1H), 3.40 (m, 1H), 3.62 (s, 3H), 3.88 (m, 1H), 4.29 (s, 4H), 4.35 (m, 1H), 5.15 (m, 1H), 6.90-7.10 (m, 3H), 7.30 (d, J=15.0 Hz, 1. H), 7.40 (d, J=15.0 Hz, 1H), 7.54 (d, J=15.0 Hz, 1H), 7.82 (m, 1H), 8.15 (m, 1H). MS (ESI) m/z 553 (M+H)+. Anal. calcd. for C25H23F3N2O7S.0.25H2O: C, 53.91; H, 4.25; N, 5.03. Found: 53.91; H, 4.35; N, 5.05.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[NH:10][N:11]=[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:3]=12.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[S:29][CH:30]=2)O1.N1C=CC=CC=1.O>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[N:10]([C:26]3[CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[S:29][CH:30]=3)[N:11]=[C:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:3]=12
Reactant: COc1ncc(Br)c2c(C3CCCC3)n[nH]c12
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-n2nc(C3CCCC3)c3c(Br)cnc(OC)c32)cs1
Temperature: 25 °C
Reaction time: 96 h
Yield: 44.1 %

Procedure:
A suspension of 4-bromo-3-cyclopentyl-7-methoxy-1H-pyrazolo[3,4-c]pyridine (100 mg), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (181 mg), copper(II) acetate (73.6 mg) and pyridine (37.4 mg) in DMF (10 mL) was stirred at room temperature for 4 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (65 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.C([Li])CCC.[Cl:19][C:20]1[N:21]=[C:22]2[N:26]([C:27]=1[S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:24][S:23]2>C1COCC1>[Cl:19][C:20]1[N:21]=[C:22]2[N:26]([C:27]=1[S:28]([N:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1)(=[O:30])=[O:29])[CH:25]=[CH:24][S:23]2
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)Cc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 3-indolylacetic acid (175 mg, 1.00 mmol) in THF is cooled to −78° C. under nitrogen and treated portionwise with 2.5 M n-butyllithium in hexanes (0.84 mL, 2.10 mmol) over a 10 min. period. After 1 h at −78° C., the reaction mixture is treated with (6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl chloride (257 mg, 1.00 mmol) in THF, allowed to warm to ambient temperature, stirred for 24 h and concentrated in vacuo. The resultant residue is treated with 1 M aq HCl (˜2 mL) and water (3 mL) and extracted with dichloromethane. The extracts are combined, dried (MgSO4) and concentrated in vacuo. Chromatography of this residue, eluting with ethyl acetate, affords the title compound as a light tan solid, 32 mg, mp 220-222° C. (darkens>200° C.), identified by mass spectral and NMR analyses.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:20])([F:19])[C:9]1[C:14]([C:15](OC)=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1.C(OCC)(=O)C.O>C1COCC1>[F:19][C:8]([F:7])([F:20])[C:9]1[CH:10]=[CH:11][N:12]=[CH:13][C:14]=1[CH2:15][OH:16]
Reactant: COC(=O)c1cnccc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCc1cnccc1C(F)(F)F
Temperature: -50 °C
Reaction time: 3 h
Yield: 34.6 %

Procedure:
A solution of 0.37 g (9.7 mmoles) of lithium aluminum hydride dissolved in 100 ml of THF was cooled to −50° C. Thereto was gradually added dropwise a solution of 2.0 g (9.8 mmoles) of methyl 4-trifluoromethylnicotinate dissolved in 30 ml of THF. The mixture was stirred at −50° C. for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, ethyl acetate was added, followed by stirring for a while. Water was added, followed by stirring for a while. The reaction mixture was filtered under vacuum. The filtrate was extracted with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.6 g (yield: 35.3%) of (4-trifluoromethylpyridin-3-yl)-methanol as a yellow oily substance.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH:21]([OH:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>ClCCl.CS(C)=O>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[C:21](=[O:26])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1CCN(Cc2ccccc2)CC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC1CCN(Cc2ccccc2)CC1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
To a solution of the product from Method D (9.8 grams/0.026 mol) and 31.7 mL of diisopropylethylamine dissolved in 250 mL of dichloromethane and cooled to 0° C. was added (dropwise) 12.4 grams of SO3 pyridine complex dissolved in 153 mL of dimethylsulfoxide over a 40 minute period. Once added, the reaction stirred for 1.5 hours at room temperature and was then quenched upon addition of 200 mL of saturated NaHCO3 (aq). The dichloromethane was removed in vacuo and the remaining aqueous residue extracted four times with diisopropyl ether (150 mL). The combined ether layers were washed four times with water (100 mL), dried over Na2SO4 and concentrated to dryness in vacuo affording 3.81 grams (72.97%) of the title compound as yellow oil. LRMS: 204 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([NH:11][CH:12]2[CH2:14][CH2:13]2)[CH:3]=1.[H][H].[Br:17][CH:18]([CH3:22])[C:19](Cl)=[O:20].C(=O)([O-])O.[Na+]>CO.[Ni].COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:19](=[O:20])[CH:18]([Br:17])[CH3:22])=[C:4]([NH:11][CH:12]2[CH2:14][CH2:13]2)[CH:3]=1
Reactant: CC(Br)C(=O)Cl
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1NC1CC1
Agent: [Ni]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: CC(Br)C(=O)Nc1ccc(Cl)cc1NC1CC1
Temperature: -60 °C
Reaction time: 2 h

Procedure:
4-Chloro-2-cyclopropylaminonitrobenzene (2.10 g, 0.01 mol) was hydrogenated in 100 ml of methanol with Raney nickel catalysis, using 1 atm hydrogen. After the calculated amount of hydrogen had been taken up, the process was stopped, the catalyst was removed by filtration with suction, and the solvent was stripped off in vacuo. To remove water completely, the mixture was taken up twice in methanol and reconcentrated. 4-Chloro-2-cyclopropylaminoaniline (1.80 g), which remained in the form of a brown oil, was dissolved in 50 ml of anhydrous 1,2-dimethoxyethane and cooled to −60° C., with stirring. A solution of 1.1 ml (0.01 mol) of 2-bromopropionyl chloride in 5 ml of anhydrous 1,2-dimethoxyethane was slowly added dropwise, and stirring of the reaction mixture was continued for 2 hours at −60-−70° C. The mixture was then allowed to warm to approx. −20° C. and poured into 150 ml of ice-cold, saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted twice using ethyl acetate, and the organic phase was washed once with water, dried (sodium sulfate) and concentrated in vacuo. After crystallization with diethyl ether/pentane, 2.51 g (79%) of the desired product of melting point 130° C. remained.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(Cl)=[O:13].[CH3:16][NH2:17]>C1(C)C=CC=CC=1>[CH3:16][NH:17][C:12]([O:11][C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=12)=[O:13]
Reactant: O=C(Cl)Cl
Reactant: Oc1cccc2ccccc12
Reactant: CN
Solvent: Cc1ccccc1
Product: CNC(=O)Oc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
A stirred solution of 1-naphthol (86.5 g, 0.6 mole) in 500 g of toluene was heated under nitrogen to 98° C. Phosgene (79.9 g, 0.8 mole) and methylamine (22.0 g, 0.7 mole) were then metered into this solution concurrently and gradually over a period of approximately 6.5 hours. The reaction mixture was filtered hot. The filtrate was then allowed to cool to room temperature, and the crystallized carbaryl was recovered by filtration. The yield of 1-naphthyl methylcarbamate was 78%.
Reaction SMILES: [OH2:1].S(=O)(=O)(O)O.[OH:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[C:9]#[CH:10]>CO>[OH:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[C:9](=[O:1])[CH3:10]
Reactant: O
Reactant: C#CC(C)(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(=O)C(C)(O)c1ccccc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
The title compound is prepared by using a modified method of G. F. Hennion and B. R. Fleck, J. Amer. Chem. Soc., 77,3258(1955). To a mixture of methanol(5 ml), water (0.2 ml), sulfuric acid (100 mg), and mercuric sulfate (100 mg) is added at 55° C. a solution of 3-hydroxy-3-phenyl-1-butyne (2 g) in 90% aqueous methanol (5 ml) over a period of 90 min. The reaction is slightly exothermic, and the inside temperature is maintained at 55°-57° C. During the reaction time, 50 mg of mercuric sulfate is added. When addition of the acetylenic component is complete, another portion (50 mg) of mercuric sulfate is added, and the mixture is stirred at 55° C. for 1 hour. During this time 1 ml of water is added. After cooling, the reaction mixture is poured into ice-water and extracted with diethyl ether. The combined extracts are washed with water, dried over magnesium sulfate, filtered and evaporated. The resultant oil is chromatographed on silica gel using benzene. The appropriate eluates are evaporated to give 0.5 g of the title compound, ir(CHCl3)3450 and 1751 cm-1 and nmr(CDCl3) δ 1.75(s), 2.08(s), 4.50(s) and 7.40(m).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)=O)=[C:9]([C:25]#[N:26])[C:8]([CH2:27][CH3:28])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:29](C)[Na].OO.C(O)(=O)C>C(O)C.O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=4)=[N:26][C:25](=[O:29])[C:9]3=[C:8]([CH2:27][CH3:28])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO[Na]
Reactant: CCc1nn(C2CCCC2)c(NC(=O)Cc2ccc(OC)c(OC)c2)c1C#N
Agent: OO
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(OC)c(OC)c3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To a mixture of 1-cyclopentyl-3-ethyl-4-cyano-5-[(3,4-dimethoxyphenylmethyl)carbonylamino]-1H-pyrazole (1.0 g, 2.7 mmol), ethanol (500 ml), and NaOCH3 (0.3 g) was added 30% H2O2 (4 ml). The reaction mixture was stirred at room temperature overnight, additional 30% H2O2 (3 equivalents) was added and the reaction mixture was refluxed on a steam bath for 1 hour. Starting material was still present so an additional 3 equivalents of 30% H2O2 was added and the reaction mixture was refluxed for 4 hours. The reaction mixture was stripped to dryness, treated with acetic acid and ethanol and again was stripped to dryness. The oily residue was dissolved in ethanol, water was added and the solution was cooled in an ice-bath. A solid formed which was collected by filtration and dried at 90° C. to afford 0.3 g (30%) of 1-cyclopentyl-3-ethyl-6-(3,4-dimethoxyphenylmethyl)-pyrazolo[3,4-d)pyrimidin-4-one, 1/10 hydrate, as a light yellow solid, m.p. 148°-149° C.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][C@@H:37]([OH:40])[CH2:36]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][C@@H:37]([OH:40])[CH2:36]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: NCCCCN1CC[C@@H](O)C1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CC[C@@H](O)C3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and (R)-1-(4-amino-butyl)-pyrrolidin-3-ol by the procedure analogous to Example 6. HPLC ret. time: 3.2 minutes. 1H NMR (400 MHz, CD3OD) δ 7.19 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.0, 10 Hz), 5.45 (s, 2H), 4.34 (m, 1H), 3.23 (m, 2H), 2.86 (dd, 1H, J=6.0, 10.4 Hz), 2.78 (m, 1H), 2.65-2.54 (m, 4H), 2.25 (s, 3H), 2.14 (m, 1H), 1.73 (m, 1H), 1.56 (m, 4H) ppm; MS (APCI, m/z): 484 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([OH:12])[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH:15]=2)[CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30]([Cl:33])(=[O:32])=[O:31]>CN(C)C1C=CN=CC=1.ClCCl>[ClH:33].[CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([O:12][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH:15]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(CC2=Cc3ccccc32)CC[C@H]1O
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(CC2=Cc3ccccc32)CC[C@H]1OS(C)(=O)=O
Product: Cl
Reaction time: 30 h

Procedure:
3.8 g (13 mmol) of trans-4-hydroxy-1-[(benzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester, 3.6 ml (26 mmol) of triethylamine and 1.8 g (14 mmol) of 4-dimethylaminopyridine are introduced into 100 ml of dichloromethane. 1.1 ml of methanesulphonic acid chloride are added thereto at room temperature. Stirring is then carried out for 30 hours, and the reaction mixture is diluted with dichloromethane, washed 3 times with water and dried over sodium sulphate. The crude product is purified by chromatography on silica gel. The purified product is converted into the hydrochloride with ethanolic hydrochloric acid and crystallised by adding diethyl ether. Trans-1-[(benzocyclobuten-1-yl)methyl]-4-methanesulphonyloxypiperidine-3-carboxylic acid ethyl ester hydrochloride of m.p. 145°-146° C. is obtained.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C1(C)C=CC=CC=1.C([O:22]CC)C>C(Cl)(Cl)Cl.C(#N)C.C(=O)([O-])[O-].[Ag+2]>[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH2:2][OH:22]
Reactant: CCOCC
Reactant: O=C(CBr)OCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 46 %

Procedure:
To a mixture of pentanoracid 7 (600 mg; 1.2 mmol), silver carbonate (440 mg; 1.6 mmol) in a mixture of chloroform (10 ml) and acetonitrile (7 ml), benzyl bromacetate (260 μl; 1.6 mmol) was added and the reaction mixture was stirred for 28 hours at room temperature. The course of the reaction was monitored by TLC (toluene/diethyl ether 6:1). The reaction mixture was then filtered through diatomaceous earth and the filtrate was worked-up and the product was purified by analogical procedure as in the preparation of 21-oxoacid benzyl glycolate. The obtained crude pentanoracid benzyl glycolate (358 mg; 46%) having m.p. 156-157° C. (methanol), [α]D=+57° (c=0.31) was used in the next step.
Reaction SMILES: C(=O)=O.[CH3:4][C:5](C)=[O:6].[CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1.[H-].[Na+].C1OC1>O1CCCC1>[OH:6][CH2:5][CH2:4][N:19]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:20]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CC(C)=O
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CO1
Product: OCCn1c2ccccc2c2ccccc21
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A 1-liter three-necked round bottom flask was equipped with a mechanical stirrer, an addition funnel, Dry Ice/acetone reflux condenser and a means for providing nitrogen atmosphere. To the flask were added 67 g (0.4 mole) of carbazole, 11 g (0.44 mole) of sodium hydride and 0.5 liter of dry tetrahydrofuran. After stirring vigorously at 0° C. for about 2.5 hours, 18 g (0.4 mole) of ethylene oxide was added dropwise to the reaction mixture over a period of 1 hour at 0° C. After the addition, stirring was continued for additional 5 hours and the tetrahydrofuran was evaporated. The residue was fully washed with water and then recrystallized from ether to give 80 g of N-(2-hydroxyethyl)-carbazole.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=1[CH2:9]O.O>C(Cl)Cl>[Br:2][CH2:9][C:8]1[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:7]=1[O:6][CH3:5]
Reactant: COc1ccc(OC)c(CO)c1
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClCCl
Product: COc1ccc(OC)c(CBr)c1
Yield: 173.4 %

Procedure:
A solution of phosphorous tribromide (5.74 ml, 60.4 mmol) in anhydrous DCM (90 ml) was added over 20 min to a cooled, stirred solution of 2,5-dimethoxybenzyl alcohol (25.0 g, 148.8 mmol) in DCM (180 ml), maintaining the temperature between −5° C. and 0° C. Following the addition, the reaction was stirred at this temperature for a further 20 min. when water (200 ml) was added. After separation of the layers, the organic was washed with water (3×200 ml), dried with magnesium sulfate and evaporated to dryness under reduced pressure. The resulting crude product was crystallised from diethyl ether/heptane to afford 2-bromomethyl-1,4-dimethoxy-benzene (24.2 g, 72%).
Reaction SMILES: C([O:8][C:9](=[O:36])[CH:10]([NH:15][C:16](=[O:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[O:26])=[CH:20][CH:19]=1)[CH2:11]C(C)C)C1C=CC=CC=1.[CH2:37]1[CH2:41]OC[CH2:38]1>CO.[OH-].[OH-].[Pd+2]>[CH3:11][C:10]([NH:15][C:16](=[O:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[O:26])=[CH:20][CH:19]=1)([CH2:38][CH2:37][CH3:41])[C:9]([OH:8])=[O:36]
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C(=O)OCc2ccccc2)cc1
Reactant: C1CCOC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCC(C)(NC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)cc1)C(=O)O

Procedure:
A mixture of 4-methyl-2-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-pentanoic acid benzyl ester (4.0 g) and palladium hydroxide on carbon (1.0 g) in 200 ml of MeOH and 200 ml of THF was shaken on a Parr apparatus under 30 p.s.i. of H2. After 2 h the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give 3.6 g of the title compound as a white solid. MS [M+1]+398.3; 1H nmr (400 MHz, DMSO-d6) δ0.79 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.4 Hz, 3H), 1.44-1.63 (m, 3H), 2.21 (s, 3H), 3.36-3.40 (m, 2H), 4.15-4.20 (m, 1H), 6.91 (t, 1H), 7.09-7.14 (m, 4H), 7.33 (d, 2H), 7.81 (d, 1H), 7.89 (s, 1H), 8.26 (d, 1H), 8.97 (s, 1H).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].C(O[B:10]1[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]1)(C)C.[C-:19]#[C-].[Li+].[Li+]>C1COCC1>[CH3:16][C:13]1([CH3:15])[C:12]([CH3:17])([CH3:18])[O:11][B:10]([C:2]#[C:3][CH:4]([CH3:5])[CH3:19])[O:14]1
Reactant: [Li]CCCC
Reactant: [C-]#[C-]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C#CB1OC(C)(C)C(C)(C)O1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Ia (7.0 g, 50 mmol) in dry THF (25 mL) at −78° C. was added n-BuLi (1.6 M in n-hexane, 62.5 mL, 100 mmol). After being stirred for 1 hour at −78° C., the reaction mixture was warmed to room temperature and stirred for 1 hour at that temperature. Another flask was charged with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.8 mL, 38 mmol) in dry THF (50 mL) under argon atmosphere, and the reaction mixture was cooled to −78° C. The lithium acetylide from the first flask, which was cooled to −78° C., was slowly added to the second by a double-ended needle. The mixture was stirred at −78° C. for 2 hours, after which anhydrous HCI (100 mmol) was added. Then, reaction mixture was warmed to room temperature. After removal of the precipitated LiCI by filtration and removal of solvents under reduced pressure, the residue was purified by distillation (113-115° C./7 mbar) to afford IIIa (5.9 g, 80%) as an oil.