Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([F:21])[CH:8]=1)[OH:6])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:9]([F:21])[CH:8]=1)[OH:6]
Reactant: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H](O)c1ccc(OCc2ccccc2)c(F)c1
Reaction time: 1 h
Yield: 69.7 %

Procedure:
A solution of (1R)-2-azido-1-[4-(benzyloxy)-3-fluorophenyl]ethanol (410 mg) in THF (8 mL) and water (2 mL) was treated with PPh3 (410 mg) and stirred for 1 h prior to addition of a further portion of PPh3 (220 mg). After stirring for a further 4 h the reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The organic phase was washed three times with 5% NaHCO3(aq), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with DCM, 1% MeOH in DCM, 2% MeOH in DCM, 5% MeOH containing 0.5% Et3N in DCM, and finally 20% MeOH containing 1% Et3N in DCM) to give the title compound (260 mg). LCMS RT=2.16 min.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)C(O)=O.CN(C)C=O.C(Cl)(=O)[C:38]([Cl:40])=[O:39]>ClCCl>[O:1]=[C:2]1[C:10]2([C:11]3=[CH:21][C:20]4[CH2:19][CH2:18][O:17][C:16]=4[CH:15]=[C:12]3[O:13][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:25][C:24]=1[C:38]([Cl:40])=[O:39]
Reactant: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (2.13 g, 5.1 mmol) and N,N-dimethylformamide (0.001 mL, catalytic amount) in anhydrous dichloromethane (30 mL) was treated with oxalyl chloride (4.50 mL, 5.1 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The crude product was concentrated in vacuo to afford 3-(((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride as a light yellow solid. A solution of 3-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride (0.27 g, 0.6 mmol), cyclohexanemethylamine (0.17 mL, 1.3 mmol), triethylamine (0.44 mL, 3.2 mmol), and 4-(dimethylamino)pyridine (0.005 g, catalytic amount) in anhydrous dichloromethane (5 mL), was stirred at ambient temperature for 20 h under nitrogen. The reaction mixture was diluted with dichloromethane (10 mL) and aqueous citric acid (10 mL) and the phases were separated. The organic phase was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0% to 100% gradient) to afford N-(cyclohexylmethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.33 g, 65%) as a colourless solid: 1H NMR (300 MHz, CDCl3) δ7.80 (s, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.48-7.37 (m, 2H), 7.23-7.15 (m, 2H), 7.08-7.00 (m, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 6.19-6.09 (m, 1H), 5.08 (d, J=15.7 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.91 (d, J=15.7 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.55 (t, J=8.6 Hz, 2H), 3.33-3.23 (m, 2H), 3.07-2.95 (m, 2H), 1.82-1.64 (m, 5H), 1.34-1.13 (m, 4H), 1.07-0.86 (m, 2H); MS (ES+) m/z 509.0 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][CH:12]=[C:13]([CH2:15][O:16][CH3:17])[N:14]=2)=[CH:6][CH:5]=1.CS(O)(=O)=O.CC1(C)[O:28][CH:27]([CH2:29]O)[CH2:26][O:25]1.O>CN(C=O)C>[CH3:17][O:16][CH2:15][C:13]1[N:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:29][CH:27]([OH:28])[CH2:26][OH:25])=[CH:9][CH:8]=2)[NH:11][CH:12]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: COCc1c[nH]c(-c2ccc(O)cc2)n1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1c[nH]c(-c2ccc(OCC(O)CO)cc2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
Under N2, a mixture of NaH (1.5 g, 0.037 mol), 60% oil dispersion), DMF (45 mol) and 89 (6.8 g, 0.033 mol) was heated at 80° C. for 30 minutes and then a solution of 2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane methansulfonate (8.4 g, 0.04 mol) in DMF (25 ml) was added dropwise. After the addition, the mixture was heated at 120° C. with stirring for 18 hours. The mixture was then poured into H2O and the solution extracted with EtOAc (4×). The combined organic extracts were backwashed with H2O, 5% NaOH, dried, filtered and concentrated to dryness. The residue was combined with acetone (75 ml) and 3N HCl (75 ml) and the solution heated on a steam bath for 30 minutes. After cooling, the solution was adjusted to pH 10 and extracted with 10% CH3OH--CHCl3. The combined extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product eluted with 10% CH3OH--CHCl3 to yield 1.7 g of 90 (18%); m.p. 154°-56° C. (isoProOH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH2:10]Cl)=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH2:10][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:4][CH:3]=1
Reactant: OC(CCCl)c1ccc(Br)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: OC(CCn1ccnc1)c1ccc(Br)cc1
Yield: 44 %

Procedure:
A solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol* (1.5 g, 6.01 mmol) and imidazole (1.23 g, 18.03 mmol) in dimethylformamide (18 ml) was heated at 100° C. for 18 hrs then partitioned between water and ethyl acetate. The organic extracts were combined, dried (MgSO4), filtered, concentrated and purified by column chromatography (SiO2), eluting with methanol:dichloromethane (2:98) to methanol:dichloromethane (6:94) to afford the title compound (0.75 g, 44% yield). LC/MS: (PS-B3) Rt 2.48 [M+H]+ 281.14, 283.11.
Reaction SMILES: [CH2:1]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:19]([N:21](CC)CC)C>C(#N)C>[C:19]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:13]=1)#[N:21]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCc1cccc[n+]1[O-]
Solvent: CC#N
Product: CCCCCCCCCCCc1cccc(C#N)n1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
To a solution of 10.0 g (40 mmol) of 2-n-undecylpyridine N-oxide and 8.10 g (80 mmol) of triethylamine dissolved in 40 ml of acetonitrile was dropwise added 15.8 g of trimethylsilylanilide while stirring at room temperature. After the dropwise addition, the mixture was refluxed for 67 hours, concentrated under a reduced pressure, followed by separation by silica gel column chromatography (ethyl acetate:hexane=1:9) to give 5.40 g of an oily product (yield 52.1%).
Reaction SMILES: N#N.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10].[Li]CCCC.CON(C)[C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[O:20]>C1COCC1>[C:30]([O:29][C:27]([N:23]1[CH2:24][CH2:25][CH2:26][C@@H:21]([C:19](=[O:20])[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[C:5]=2[F:10])[CH2:22]1)=[O:28])([CH3:33])([CH3:32])[CH3:31].[F:3][C:4]1[C:5]([F:10])=[CH:6][CH:7]=[CH:8][C:9]=1[C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[O:20]
Reactant: Fc1ccccc1F
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(F)c2F)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Under protection of N2, 1,2-difluorobenzene (22 g, 0.19 mol) in anhydrous THF (300 mL) was cooled to −78° C. and 2.5 M n-BuLi solution in hexanes (76 mL, 0.19 mol) was added dropwise slowly. The reaction mixture was stirred at −78° C. for 1 hr, the solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (47.7 g, 0.175 mol) in anhydrous THF (200 mL) was slowly added dropwise. The reaction mixture warmed to rt and stirred for 2 hrs. The mixture was quenched with saturated NH4Cl (300 mL), extracted three times with ethyl acetate, and dried over Na2SO4. Solvent removal and flash column chromatography afforded crude (R)-tert-butyl 3-(2,3-difluorobenzoyl)piperidine-1-carboxylate (R)-tert-butyl 3-(2,3-difluorobenzoyl)piperidine-1-carboxylate (40 g, 70%). 1H NMR (CDCl3, 400 MHz) δ 7.51 (m, 1H), 7.34 (m, 1H), 7.19 (m, 1H), 4.19 (d, 1H), 3.96 (m, 1H), 3.23 (m, 1H), 3.04 (t, 1H), 2.85 (m, 1H), 2.06 (m, 1H), 1.75 (m, 1H), 1.62 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].[OH:13][CH:14]1[CH2:17][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[CH2:15]1>ClCCl>[CH3:11][S:8]([O:13][CH:14]1[CH2:15][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[CH2:17]1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(O)C2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC(OS(C)(=O)=O)C2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.76 mL (5.49 mmol) of triethylamine and then 0.43 mL (5.49 mmol) of mesyl chloride are added to a solution of 1.52 g (4.99 mmol) of tert-butyl 2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate, obtained in step 6.1., in 45 mL of dichloromethane. The reaction medium is stirred at room temperature for 1 hour 30 minutes. After evaporating off the solvent, water is added to the reaction medium, the aqueous phase is separated out and extracted several times with dichloromethane, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. After evaporating off the solvent, 1.90 g of product are obtained in the form of a brown oil, which is used without further purification in the following step.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[O:17][CH:18]([C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1)[CH2:19][CH2:20][CH2:21][N:22]1[CH2:29][CH:28]2[O:30][CH:24]([CH2:25][NH:26][CH2:27]2)[CH2:23]1>CC#N.C(Cl)(Cl)Cl>[C:35]([C:34]1[CH:33]=[CH:32][C:31]([CH:18]([O:17][C:16]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:19][CH2:20][CH2:21][N:22]2[CH2:29][CH:28]3[O:30][CH:24]([CH2:25][N:26]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH2:27]3)[CH2:23]2)=[CH:38][CH:37]=1)#[N:36]
Reactant: COc1ccc(OC(CCCN2CC3CNCC(C2)O3)c2ccc(C#N)cc2)cc1OC
Reactant: CCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCNC(=O)N1CC2CN(CCCC(Oc3ccc(OC)c(OC)c3)c3ccc(C#N)cc3)CC(C1)O2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of ethyl isocyanate (18.8 mg, 0.25 mmol) in MeCN (2 mL) was added, together with K2CO3 (34.5 mg, 0.25 mmol), to a solution of 4-[1-(3,4-dimethoxyphenoxy)-4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]benzonitrile (Preparation H; 109.4 mg, 0.25 mmol) in chloroform (0.5 mL). The reaction mixture was stirred at rt for 4 days before being added to a solid phase extraction plug (SiO2, 0.5 g). The plug was washed with CHCl3:MeCN (2.5 mL of 80:20), and the product was finally eluted with CHCl3:MeOH (3×2.5 mL of 95:5) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:16]O)[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>ClCCl>[Br:38][CH2:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:9]=1[N:3]1[C:2]([Cl:1])=[N:6][N:5]([CH3:7])[C:4]1=[O:8]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cccc(CO)c1-n1c(Cl)nn(C)c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(CBr)c1-n1c(Cl)nn(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of the title compound of Step D (3.0 g, 12 mmol) in dichloromethane (56 mL) cooled to 0° C. under a nitrogen atmosphere was added triphenylphosphine (3.72 g, 14 mmol) followed by carbon tetrabromide (5.9 g, 18 mmol). The mixture was allowed to warm to room temperature and was stirred for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (2:1 hexanes:ethyl acetate) to afford 3.19 g of the title compound of Step E as a light yellow powder. 1H NMR (CDCl3): δ 7.3-7.39 (m,3H), 4.35 (AB q,2H), 3.56 (s,3H), 2.16 (s,3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=2)[C:21]([N:23]([CH2:25][C:26]([OH:28])=O)[CH3:24])=[O:22])=[CH:12][CH:11]=1.[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34]>CN1C(=O)CCC1>[CH3:32][S:33]([NH:36][C:26](=[O:28])[CH2:25][N:23]([CH3:24])[C:21](=[O:22])[C:20]1[CH:29]=[CH:30][CH:31]=[C:18]([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:3]3[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:11][CH:12]=2)[CH:19]=1)(=[O:35])=[O:34]
Reactant: CN(CC(=O)O)C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Reactant: CS(N)(=O)=O
Solvent: CN1CCCC1=O
Product: CN(CC(=O)NS(C)(=O)=O)C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.8 %

Procedure:
1,1-Carbonyldiimidazole (671 mg, 4.14 mmol) was added to a stirred solution of {[3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzoyl]-methyl-amino}-acetic acid (1.1 g, 3.07 mmol) in 5 mL NMP in an ice bath under argon for 3 hrs. To this mixture was added methanesulfonamide (437 mg, 4.6 mmol) and 1,8-diazobicyclo[5.4.0]undec-7-ene (0.684 mL, 4.6 mmol). The reaction was stirred at RT overnight. An additional 0.5 equiv. each of 1,1-carbonyldiimidazole (335 mg, 2.07 mmol), methanesulfonamide (197 mg, 2.07 mmol) and 1,8-diazobicyclo[5.4.0]undec-7-ene (0.34 mL, 2.07 mmol) were added and let stir over the weekend. The reaction mixture was concentrated, dissolved in 250 mL ethyl acetate, washed with H2O and concentrated. The crude product was purified by flash chromatography with a 0-25% gradient of ethyl acetate/MeOH/AcOH (95:5:1) in CH2Cl2 and lyophilized to yield 153 mg (38.6%) of N-(2-methanesulfonylamino-2-oxo-ethyl)-N-methyl-3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzamide as an amorphous solid. LC-MS (ES) calculated for C24H21F2NO5S, 506.50; found m/z 507 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][O:12][CH2:11]2)[CH:8]=1)([O-:3])=[O:2].C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl>[CH3:26][S:23]([O:15][CH2:14][C:10]1([CH2:9][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]2)[CH2:13][O:12][CH2:11]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cnn(CC2(CO)COC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(Cn2cc([N+](=O)[O-])cn2)COC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(3-((4-nitro-1H-pyrazol-1-yl)methyl)oxetan-3-yl)methanol (0.6 g, 2.8 mmol) was dissolved in DCM (16 ml) with triethylamine (0.778 mL, 5.6 mmol) and the reaction was cooled at 0° C. Mesyl chloride (0.415 g, 3.62 mmol) was added dropwise and the reaction was allowed to reach rt overnight. The mixture was diluted in DCM (25 mL), washed with water (20 mL) and the water re-extracted with DCM (20 mL). The combined organics were dried over Na2SO4, filtered and the solvent removed under vacuum. (3-((4-nitro-1H-pyrazol-1-yl)methyl)oxetan-3-yl)methyl methanesulfonate was obtained as a yellowish oil (0.9 g, quantitative yield).
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:10][CH2:11][N:12]([CH2:26][C:27]([OH:29])=[O:28])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=[O:18])[CH2:6][C:7]([OH:9])=O)([OH:3])=[O:2].N1C=CC=CC=1>C(OC(=O)C)(=O)C>[O:9]=[C:7]1[CH2:6][N:5]([CH2:10][CH2:11][N:12]([CH2:13][CH2:14][N:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=[O:18])[CH2:26][C:27]([OH:29])=[O:28])[CH2:4][C:1](=[O:2])[O:3]1
Reactant: CCOC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CN(CCN(CCN1CC(=O)OC(=O)C1)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 21.1 g (50 mmol) of N3,N6-bis(carboxymethyl)-N9-(ethoxy-carbonylmethyl)-3,6,9-triazaundecanedioic acid in 250 ml of acetic anhydride is allowed to stir for three days at room temperature after the addition of 42.2 ml of pyridine. Then, the precipitate is suctioned off, washed three times with 50 ml of acetic anhydride each and then stirred for several hours with absolute diethyl ether. After suctioning off, washing with absolute diethyl ether and drying in a vacuum at 40° C., 18.0 g (=89% of theory) of a white powder with a melting point of 195-196° C. is obtained.
Reaction SMILES: Br[C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:22])[C@:16]1([CH3:17])[C:11]([CH2:12][C@@H:13]([CH3:21])[CH2:14][CH2:15]1)=[CH:10][CH2:9]3.[OH-:23].[Na+].Cl>CN(C)C=O.O>[OH:23][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:22])[C@:16]1([CH3:17])[C:11]([CH2:12][C@@H:13]([CH3:21])[CH2:14][CH2:15]1)=[CH:10][CH2:9]3
Reactant: [OH-]
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](Br)C[C@@H]32)C1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](O)C[C@@H]32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
16α-Bromo-3β-methylandrost-5-en-17-one (1.00 g, 2.74 ,mmol) was dissolved in dimethylformamide (90 mL). Sodium hydroxide (165 mg, 4.1 mmol) in water (10 mL) was added and the solution stirred for 2 h. at room temperature. The solution was poured into 1% HCl (200 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with 5% sodium biocarbonate, water, then dried over magnesium sulfate and filtered. Evaporation gave a pale yellow solid which was chromatographed on flash silica gel and eluted with ether/hexane (10/90). Recrystallization from ether gave 0.54 g (65%) 16α-hydroxy-3β-methylandrost-5-en-17-one mp 166°-168° C.; NMR (DMSO-d6) δ 5.30 (br s, 1H, H-3), 4.38 (t, 1H, 16β-H), 2.0-1.05 (m, complex), 0.98 (s, 3H, C-19 Me), 0.95 (d, J=8 Hz, 3H, C-3 Me), 0.87 (s, 3H, C-18 Me); IR (KBr) 3440, 2900, 1735, 1445, 1365, 1010; MS 302 (m+, 100), 287(24), 274(7), 259(7), 241(7), 230(72), 215(41), 159(31); Anal. Calcd for C20 H30O2 : C, 79.42; H, 9.99. Found: C, 79.24; H, 10.04.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([O:15][CH3:16])=[N:13][CH:14]=2)[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[CH3:8][C@H:6]1[N:7]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:10]=[C:11]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:12]([O:15][CH3:16])=[N:13][CH:14]=2)[CH2:5]1
Reactant: COc1ncc(N2C[C@@H](C)N[C@@H](C)C2)cc1C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncc(N2C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C2)cc1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 1,1-dimethylethyl 5-[cis-3,5-dimethyl-1-piperazinyl]-2-(methyloxy)-3-pyridinecarboxylate (D24) (500 mg, 1.56 mmol), potassium carbonate (430 mg, 3.12 mmol) and benzyl bromide (266 mg, 1.56 mmol) in N,N-dimethylformamide (10 ml) was stirred at 80° C. for 4 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase washed with water, dried and evaporated. Purification by flash chromatography eluting with 5-20% ethyl acetate in hexanes gave the title compound (D25). MS (ES+) m/e 412 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][N:15]([CH2:26][C:27]([OH:29])=O)[C:16]3[S:20][N:19]=[C:18]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)[N:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:37]([CH3:39])[CH3:38]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][N:15]([C:16]3[S:20][N:19]=[C:18]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)[N:17]=3)[CH2:26][C:27]([N:37]([CH3:39])[CH3:38])=[O:29])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N(CCCN(CC(=O)O)c1nc(-n2ccnc2)ns1)Cc1ccc2c(c1)OCO2
Product: CN(C)C(=O)CN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1

Procedure:
2-[{3-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-propyl}-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-N,N-dimethyl-acetamide was prepared following the procedures described in the preparation of Example 56 using [[3-(benzo[1,3]dioxol-5-ylmethyl-tert-butoxycarbonyl-amino)-propyl]-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetic acid and Me2NH. [M+H]+ 443.99; 1H NMR (400 MHz, d6-DMSO) δ 8.34 (s, 1H), 7.75 (s, 1H), 7.12 (s, 1H), 6.99 (s, 1H), 6.87 (m, 2H), 6.03 (s, 2H), 4.51 (br s, 1H), 3.78 (br s, 2H), 3.38 (br s, 2H), 3.05 (s, 3H), 2.89 (s, 3H), 2.75 (m, 2H), 2.53 (m, 2H), 1.89 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:15]=[C:14]([O:16]C)[CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].B(Br)(Br)Br.C(O)C>ClCCl>[Cl:1][C:2]1[C:3]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1sc2ccc(OC)cc2c1Cl
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1sc2ccc(O)cc2c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
A stirred solution of ethyl 3-chloro-5-methoxybenzo[b]thiophene-2-carboxylate (20.0 g) in dichloromethane (80 ml) at −20° C. under an atmosphere of nitrogen was treated with boron tribromide (1M solution in dichloromethane; 90 ml) and the solution allowed to warm up to room temperature slowly. After 2 hours the mixture was carefully poured into ethanol (400 ml) and left to stand for 10 minutes. The solvent was evaporated under reduced pressure and the residue dissolved in ethyl acetate (500 ml). The resulting solution was washed with water (300 ml), dried over sodium sulphate and the solvent evaporated under reduced pressure to give ethyl 3-chloro-5-hydroxybenzo[b]thiophene-2-carboxylate (18.68 g) as an off-white solid; m.p. 160-161° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(OCC)(=O)C>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH2:7][NH:8][C:19](=[O:21])[CH3:20])[CH3:11]
Reactant: CCOC(CCCN)OCC
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(CCCNC(C)=O)OCC
Reaction time: 2 h

Procedure:
4,4-Diethoxybutylamine (3.0 g, 18.61 mmol) and triethylamine (7.85 ml, 55.83 mmol) were dissolved in 250 ml of ethyl acetate. At 10° C., acetic anhydride (1.75 ml, 18.61 mmol) was added, and stirring was continued for 2 h. The cooling bath was removed after 1 h. The reaction mixture was concentrated. Yield: 1.526 g. The product was directly reacted further.