Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11]([CH:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[C:15]([O:17][CH3:18])=[O:16])(O)[CH2:10]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.N1(C2CCCCCCCCCC2)CCCCCCCCCN1>C(Cl)Cl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][C:11](=[C:14]([C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)[C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)=[CH:32][CH:31]=1
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1(O)CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
A solution of 0.71 g (1.44 mmol) of methyl {1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}(3,5-difluorophenyl)acetate, 0.295 g (1.73 mmol) of methanesulfonyl anhydride, and 0.400 mL pyridine in 5 mL of CH2Cl2 was stirred at room temperature overnight. To this was added 0.400 mL of diazabicycloundecane and the solution remained stirring at room temperature. The mixture was partitioned between ether and water and the aqueous layer was washed with 20 mL of ether. The organic layers were washed with brine, combined, dried over MgSO4 and concentrated. The residue was filtered through a pad of silica gel using 20% ether-hexane to afford the title compound; 1H-NMR(CDCl3) δ 3.67 (s, 3H), 3.84 (m, 2H), 4.25 (m, 2H), 4.54 (s, 1H), 6.76 (m, 1H), 6.78 (m, 2H), 7.33 (m, 4H), 7.38 (m, 4H); Mass Spectrum: m/e =474 (M+1 35Cl, 35Cl) and 476 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:23])[C:7]([S:10]([N:13]2[CH2:17][CH2:16][C@H:15](OS(C)(=O)=O)[CH2:14]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:30]([C:34]1[CH:39]=[C:38]([SH:40])[CH:37]=[C:36]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]=1[OH:45])([CH3:33])([CH3:32])[CH3:31]>CCC(C)=O.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:23])[C:7]([S:10]([N:13]2[CH2:17][CH2:16][C@@H:15]([S:40][C:38]3[CH:37]=[C:36]([C:41]([CH3:42])([CH3:43])[CH3:44])[C:35]([OH:45])=[C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:39]=3)[CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:4]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CC[C@H](OS(C)(=O)=O)C2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)N2CC[C@@H](Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2)n1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a solution of (S)-5-(3-methanesulfonyloxy-pyrrolidine-1-sulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (Ex. 13b, 7.75 g, 21.2 mmol) and cesium carbonate (11.6 g, 31.8 mmol) in degassed MEK (85 mL) at 60° C. was added 2,6-di-tert-butyl-4-mercaptophenol (7.6 g, 31.8 mmol). The resulting solution was stirred at 60° C. for 3 h. Upon completion, as determined by HPLC, the reaction was diluted with H2O (200 mL) and Ethyl acetate (100 mL). The layers were cut and the aqueous layer was extracted with Ethyl acetate (3×100 mL). The combined organic cuts were washed with a saturated ammonium chloride solution (1×100 mL), a 50% aqueous brine solution (1×100 mL) and brine (1×100 mL), dried over Na2SO4, and concentrated under reduced pressure. Silica gel chromatography (Ethyl acetate:hexanes, 1:2) afforded 9.34 g (87%) of (R)-5-[3-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-pyrrolidine-1-sulfonyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as a white solid, mp 83-85° C. 1H-NMR (400 MHz, CDCl3): δ 7.23 (d, 1H, J=2.0 Hz), 7.21 (s, 2H), 7.17 (d, 1H, J=2.0 Hz), 5.30 (s, 1H), 3.97 (s, 3H), 3.84 (s, 3H), 3.59 (dd, 1H, J=10.4, 7.2 Hz), 3.47 (pentet, 1H, J=6.8 Hz), 3.28-3.39 (m, 2H), 3.10 (dd, 1H, J=10.4, 6.4 Hz), 2.12-2.20 (m, 1H), 1.75-1.84 (m, 1H), 1.42 (s, 18H). Anal. Calcd. for C25H36N2O5S2: C, 59.03; H, 7.13; N, 5.51; S, 12.61. Found: C, 59.63; H, 7.34; N, 5.39; S, 12.23.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH3:6])=[C:2]=[O:3].[OH:7][C@H:8]1[CH2:27][N:11]2[C:12](=[O:26])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][C@@H:10]2[CH2:9]1.O>C1COCC1.N1C=CC=CC=1>[O:26]=[C:12]1[N:11]2[CH2:27][C@H:8]([O:7][C:2](=[O:3])[NH:1][CH2:4][CH2:5][CH3:6])[CH2:9][C@H:10]2[CH2:14][N:13]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](O)CN12
Reactant: CCCN=C=O
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CCCNC(=O)O[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Yield: 25.8 %

Procedure:
1-Isocyanatopropane (30 mg, 0.4 mmol) was added to a solution of (6R,7aS)-6-Hydroxy-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 1, step e) (60 mg, 0.2 mmol) in anhydrous THF (10 mL) and pyridine (2 mL). The mixture was refluxed overnight. The mixture was cooled and poured into water (20 mL), extracted with ethyl acetate (3×20 mL). The organic layers was combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to give final compound 20 mg (26%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.60 (d, 2H, J=9.0 Hz), 7.19 (d, 2H, J=8.7 Hz), 5.35 (t, 1H, J=5.7), 4.71 (s, 1H), 4.17-4.00 (m, 3H), 3.74 (d, 1H, J=7.2 Hz), 3.22-3.12 (m, 3H), 2.23 (dd, 1H, J1=12.9 Hz, J2=3.3 Hz), 1.71-1.48 (m, 3H), 0.94 (t, 3H, J=7.2 Hz); LC-MS: 388.1 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:9]([CH:17]=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:27]I.C([Li])CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]([C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C@@H:17]1[O:18][CH2:27]1)[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](C=O)Cc1ccccc1
Reactant: ClCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: -72.5 °C
Reaction time: 0.17 h

Procedure:
A solution of 2.5 g (7.37 mmoles) of N-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninal and 0.72 mL of chloroiodomethane in 35 mL of THF was cooled to −78° C. A 4.64 mL of a solution of n-butyllithium (1.6 M in hexane, 7.42 mmoles) was added slowly, keeping the temperature below −70° C. The mixture was stirred for 10 minutes between −70 to −75° C. Two additional portions of 0.22 mL of chloroiodomethane and 1.4 mL of n-butyllithium was added sequentially and the mixture was stirred for 10 minutes between −70 to −75° C. after each addition. Four additional portions of 0.11 mL of chloroiodomethane and 0.7 mL of n-butyllithium was added sequentially and the mixture was stirred for 10 minutes between −70 to −75° C. after each addition. The mixture was warmed to room temperature for 3.5 hours. The product was quenched at below 5° C. with 24 mL of ice-cold water. The biphasic layers were separated and the aqueous layer was extracted twice with 30 mL of ethyl acetate. The combined organic layers was washed three times with 10 mL water, then with 10 mL brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2.8 g of a yellow crude oil. This crude oil (>100% yield) is a mixture of the diastereomeric epoxides N,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine and N,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanamine. The crude mixture is used directly in the next step without purification.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=[O:8])[C@H:4]([C:10]([OH:12])=[O:11])[CH2:3]1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[CH2:13]([O:8][C:7]([C@@H:5]1[C@H:4]([C:10]([OH:12])=[O:11])[CH2:3][C:2](=[O:1])[O:6]1)=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=C1C[C@@H](C(=O)O)[C@@H](C(=O)O)O1
Solvent: CC(C)=O
Product: O=C1C[C@@H](C(=O)O)[C@@H](C(=O)OCc2ccccc2)O1
Reaction time: 12 h

Procedure:
5.2 g of (2S,3R)-5-oxotetrahydrofuran-2,3-dicarboxylic acid in 88 ml of acetone was stirred with 6.5 g of 1,1'-dicyclohexylcarbodiimide at room temperature for 2 hours. 3.26 ml of benzyl alcohol was added, and the reaction solution was stirred at the same temperature for 12 hours. The insolubles were filtered off, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=4/1→chloroform/methanol=50/1] to give 7.93 g of the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH2:22]O)[CH:19]=[CH:20][CH:21]=1>>[Br:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1cccc(Br)c1
Product: N#Cc1ccnc(-n2nccc2OCc2cccc(Br)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-bromophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.22 (2H, s), 5.74 (1H, s), 7.28 (1H, d, J=7.6 Hz), 7.35 (1H, d, J=7.6 Hz), 7.42 (1H, d, J=4.4 Hz), 7.49 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=1.2 Hz), 7.64 (1H, s), 8.05 (1H, s), 8.72 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H11BrN4O, 355; Found, 355.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:9](O)[CH2:10][OH:11]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:2][C:1]1([C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)[O:11][CH2:10][CH2:9][O:3]1
Reactant: CC(=O)c1ccsc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(c2ccsc2)OCCO1
Reaction time: 16 h
Yield: 46.7 %

Procedure:
A mixture of 3-acetylthiophene (20 g), ethyleneglycol (10.54 g), p-toluenesulfonic acid (0.15 g) and toluene (200 ml) was stirred for 16 hours under reflux with removing azeotropic water by Dean-Stark trap. The mixture was cooled, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-methyl-2-(3-thienyl)-1,3-dioxolan (12.6 g). 2-Methyl-2-(3-methyl-2-(3-thienyl)-1,3-dioxolan (12.0 g) was dissolved in tetrahydrofuran (200 ml), and N,N,N',N'-tetramethylethylenediamine (1.3 ml) was added. The mixture was cooled to -78° C, and n-butyllithium (1.6M in hexane, 49 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 2 hours, and then warmed slowly to room temperature for a period of 2 hours with introducing carbon dioxide gas. The reaction mixture was concentrated under reduced pressure, and 2N hydrochloric acid (200 ml) was added. The mixture was stirred for 3 hours, and precipitated crystals were collected by filtration, washed with water and dried to give 3-acetyl-2-thiophenecarboxylic acid (10 g) as crystals.
Reaction SMILES: [NH2:1][C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=1)([CH3:13])[CH2:3][O:4][C@@:5]([CH3:12])([C:8]([F:11])([F:10])[F:9])[C:6]#[N:7].C(N[C@H](C(O)=O)CS)(=O)C.C([O-])([O-])=O.[K+].[K+]>CCO>[Br:20][C:16]1[N:15]=[C:14]([C:2]2([CH3:13])[CH2:3][O:4][C@@:5]([CH3:12])([C:8]([F:10])([F:9])[F:11])[C:6]([NH2:7])=[N:1]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(N)(CO[C@](C)(C#N)C(F)(F)F)c1cccc(Br)n1
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1(c2cccc(Br)n2)CO[C@@](C)(C(F)(F)F)C(N)=N1

Procedure:
A suspension of (R)-2-[(RS)-2-amino-2-(6-bromo-pyridin-2-yl)-propoxy]-3,3,3-trifluoro-2-methyl-propionitrile (0.688 g, 1.172 mmol), N-acetyl-L-cysteine (0.383 g, 2.344 mmol) and K2CO3 (0.356 g, 2.560 mmol) in abs. EtOH (4 ml) was stirred at 80° C. for 18 h. The reaction mixture was quenched with 10% aq. K2CO3 soln. and 3× extracted with TBME. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated to leave the title compound as a colourless solid. HPLC RtH4=0.68-0.70 min; ESIMS: 352, 354 [(M+H)].
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[O:13][CH3:14])=[CH:18][CH:17]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNCc2ccc(F)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (0.518 g, 2 mmol, Trans World Chemicals) in THF (10 mL) at room temperature was added (4-fluorophenyl)methanamine (1.00 g, 8.00 mmol, Aldrich) and triethylamine (0.56 mL, 4 mmol). The reaction mixture was stirred at rt for 1 h and quenched by the addition of 5 mL of saturated aq. NaHCO3 solution. The resulting mixture was extracted with DCM (3×50 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (ISCO system, eluting with CH2Cl2/EtOAc) to give the desired compound (0.35 g, 57%) as a white solid. 1H NMR (CD3OD) δ 7.64 (d, 1H, J=6.0 Hz), 7.60 (s, 1H), 7.40 (d, 2H, J=7.7 Hz), 7.36 (d, 1H, J=6.0 Hz), 7.08 (t, 211, J=7.7 Hz), 3.97 (s, 3H), 3.96 (s, 3H), 3.82 (s, 2H), 3.76 (s, 2H). MS (ESI): 304.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH2:11]([O:13][C:14](=[O:24])[CH2:15][NH:16][C:17]1[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:12].C(OC(=O)CNC1C([N+]([O-])=O)=CC=CN=1)C.C(N(CC)CC)C>O1CCCC1.[Pd]>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][NH:16][C:17]1[C:22]([NH:23][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:12]
Reactant: CCOC(=O)CNc1ncccc1N
Reactant: O=C(Cl)c1cccc(F)c1
Agent: [Pd]
Agent: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ncccc1NC(=O)c1cccc(F)c1
Yield: 6.6 %

Procedure:
Under a nitrogen atmosphere, 3-fluorobenzoyl chloride (12.9 g, 0.0816 mole) was added dropwise to a stirred and chilled (10°-15° C.) mixture of N-(3-amino-2-pyridinyl)glycine ethyl ester (0.0816 mole) [freshly prepared by the hydrogenation of a solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester in tetrahydrofuran over 5% palladium on carbon at room temperature], triethylamine (8.3 g, 0.0816 mole), anhydrous tetrahydrofuran (200 ml), and powdered molecular sieves. The reaction mixture was stirred at room temperature for 1 hour and was filtered. The filtrate was concentrated in vacuo and the residual solid triturated in isopropyl ether-isopropyl alcohol, giving 24.2 g (94%). Recrystallization of a 2.0-g sample gave 1.72 g of a white powder, mp 134°-135° C.
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11](=O)[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].[Br:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[C:17]([Br:22])[C:16]=1[OH:23]>CCO>[Br:14][C:15]1[CH:20]=[C:19]([N:21]2[C:11]([CH3:12])=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:1]2[CH3:2])[CH:18]=[C:17]([Br:22])[C:16]=1[OH:23]
Reactant: CCOC(=O)C(CC(C)=O)C(C)=O
Reactant: Nc1cc(Br)c(O)c(Br)c1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cc(Br)c(O)c(Br)c2)c1C

Procedure:
Utilizing the procedure outlined in Example 85, ethyl 2-acetyl-4-oxopentanoate (6.37 g, 34.2 mmol) was dissolved in 20 mL of EtOH. 2,6-dibromo-4-aminophenol (11.6g, 34.2mmol) were reacted to afford ethyl 1-(3,5-dibromo-4-hydroxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate was taken on without further purification. MS (ESI) 418 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[N:24]([CH2:25][C:26]3[C:31]([OH:32])=[CH:30][CH:29]=[C:28]([CH3:33])[N:27]=3)[C:23]3[CH:34]=[C:35]([CH3:39])[CH:36]=[C:37]([CH3:38])[C:22]=3[N:21]=2)[CH2:15][CH2:14]1)C.O.C(OC(=O)C)C>O1CCCC1>[OH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[N:24]([CH2:25][C:26]3[C:31]([OH:32])=[CH:30][CH:29]=[C:28]([CH3:33])[N:27]=3)[C:23]3[CH:34]=[C:35]([CH3:39])[CH:36]=[C:37]([CH3:38])[C:22]=3[N:21]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)CCN1CCC(Nc2nc3c(C)cc(C)cc3n2Cc2nc(C)ccc2O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c2nc(NC3CCN(CCCO)CC3)n(Cc3nc(C)ccc3O)c2c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
LiAlH4 (0.0002 mol) was added at 5° C. to a mixture of 3-{4-[1-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-4,6-dimethyl-1H-benzoimidazol-2-ylamino]-piperidin-1-yl}-propionic acid ethyl ester (r-1; 0.00009 mol; melting point: 172° C.) in tetrahydrofuran (10 ml) under N2 flow. The mixture was stirred at 5° C. for 1 hour, then at room temperature for 3 hours. A minimum of H2O and ethylacetate were added. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue was crystallized from 2-propanone/CH3CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.026 g of 2-{2-[1-(3-hydroxy-propyl)-piperidin-4-ylamino]-4,6-dimethyl-benzoimidazol-1-ylmethyl}-6-methyl-pyridin-3-ol (r-2; 68%, melting point: 209° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:17]=[CH:16][C:15](O)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2].[C:30](=O)([O-])[O-:31].[K+].[K+].BrC[C:38]([O:40][CH3:41])=[O:39].[NH4+].[Cl-]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:38]([O:40][CH3:41])=[O:39])=[CH:14][C:13]=2[O:31][CH3:30])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(O)cc2)n1-c1ccc(C(N)=O)cc1C
Reactant: COC(=O)CBr
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(-c2ccc(C(=O)OC)cc2OC)n1-c1ccc(C(N)=O)cc1C
Reaction time: 18 h
Yield: 98 %

Procedure:
3-[1-(4-Carbamoyl-2-methylphenyl)-5-(4-hydroxyphenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester 16A (synthesized according to the first three steps of Scheme 1, where Ar2=4-hydroxyphenyl, and Ar1=4-carbamoyl-2-methylphenyl) (47 mg, 0.12 mmol) was dissolved in 0.5 mL N,N-dimethylformamide. Potassium carbonate (33 mg, 0.24 mmol) was added. Methyl 2-bromoacetate (0.02 mL, 0.13 mmol) was added. After 18 hrs, the reaction was poured into NH4Cl (sat) and extracted with EtOAc (2×5 mL). The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC plate (10% IPA/CH2Cl2). The desired band (RF=0.57) was isolated and dried under high vacuum to yield 3-[1-(4-Carbamoyl-2-methylphenyl)-5-(4-methoxycarbonyl-methoxyphenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (16B) (57 mg, 98%, white powder).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[C:21]1([N:27]=[C:28]=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[C:21]1([NH:27][C:28]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[N:6]=[C:7]([C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[O:15])[C:8]3[S:13][CH:12]=[CH:11][C:9]=3[N:10]=2)=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Reactant: S=C=Nc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cccs1)c1nc(NCCNC(=S)Nc2ccccc2)nc2ccsc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A solution of 2-(2-aminoethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (50 mg, 0.16 mmol) in anhydrous DMF (1 mL) was treated with phenyl isothiocyanate (33 mg, 0.25 mmol), shaken at room temperature for 2 h, poured into water (20 mL) and the resulting yellow precipitate was filtered and dried in vacuo to give the title compound (44 mg, 61%) as a yellow solid.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])(OCC)OCC.C(O[C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25](=[CH:26]C(=O)[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)(=O)C.C(NC(C)C)(C)C.O>CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:1]1[CH2:28][CH2:29][C@H:30]2[C:25](=[CH:24][CH2:23][C@@H:22]3[C@@H:31]2[CH2:32][CH2:33][C@@:18]2([CH2:19][CH3:20])[C@H:21]3[CH:15]=[CH:16][C:17]2=[O:35])[CH:26]=1)[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Triethyl orthoformate (5 ml, 30 mmol) and p-Toluenesulfonic acid (50 mg, 0.26 mmol) were added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (5 g, 14.5 mmol) in EtOH (30 ml). The mixture was stirred at room temperature for 1 h. Diisopropylamine (6.3 ml, 36 mmol) was added, and the mixture was heated under reflux for 2 h, cooled to 10° C. and water (15 ml) was then added. The precipitate was filtered, washed with water and dried. The crude product was purified by flash chromatography, eluting with heptane and ethyl acetate (7:3), crystallized from heptane, and dried under vacuum to afford 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (3.18 g, yield: 71%).
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:22][O:23][C:24]([CH:26]1[CH2:30][C:29](=O)[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25].CC(C)([O-])C.[K+].O>C1COCC1>[CH3:22][O:23][C:24]([CH:26]1[CH2:30][C:29](=[CH2:2])[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25]
Reactant: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of methyltriphenylphosphonium iodide (1.25 g, 3.08 mmol) in THF (20 ml) at 0° C., 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (500 mg, 2.05 mmol) and potassium ter-butoxide (460 mg, 4.11 mmol) was added. It was stirred for overnight at room temperature. Water was added and the compound was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum. Purification by column chromatography offered 4-methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a colorless oil (0.23 g, 46%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([CH2:37][CH3:38])=[CH:34][C:35]=2[CH3:36])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:37]([C:33]1[N:32]=[CH:31][C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:39])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[C:35]([CH3:36])[CH:34]=1)[CH3:38]
Reactant: CCc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(C)c(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-ethyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M234) (156 mg, 0.28 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (73 mg, 60%).