Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([O:16][C:17](=[O:19])[CH3:18])[CH2:13][CH:12]1[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[NH:23][C:22]=1[C:31]1[NH:32][C:33]2[C:38]([C:39]=1[CH2:40][CH:41]1[CH2:45][CH:44]([O:46][C:47](=[O:49])[CH3:48])[CH2:43][N:42]1C(OCC1C=CC=CC=1)=O)=[CH:37][CH:36]=[C:35]([F:60])[CH:34]=2)=O)C1C=CC=CC=1>[Pd].CCOC(C)=O.CO>[C:17]([O:16][CH:14]1[CH2:15][NH:11][CH:12]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[NH:23][C:22]=2[C:31]2[NH:32][C:33]3[C:38]([C:39]=2[CH2:40][CH:41]2[NH:42][CH2:43][CH:44]([O:46][C:47](=[O:49])[CH3:48])[CH2:45]2)=[CH:37][CH:36]=[C:35]([F:60])[CH:34]=3)[CH2:13]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC1CC(Cc2c(-c3[nH]c4cc(F)ccc4c3CC3CC(OC(C)=O)CN3C(=O)OCc3ccccc3)[nH]c3cc(F)ccc23)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)OC1CNC(Cc2c(-c3[nH]c4cc(F)ccc4c3CC3CC(OC(C)=O)CN3)[nH]c3cc(F)ccc23)C1
Reaction time: 3 h
Yield: 102.1 %

Procedure:
A suspension containing 9 (35 g, 42.7 mmol) in 1:1 EtOAc/MeOH (400 mL) was distributed into two 500 mL Parr bottles (ca. 200 mL/each), and charged with 10% Pd-on-C (wet, 5000 mg/each, Aldrich®). The reaction mixture was pressurized to 50 PSI H2 and shaken for 3 h. The reaction mixture was filtered through a pad of Celite® and the solids were washed with EtOAc. The clarified filtrate was concentrated in vacuo to afford 24 g of 10 as an off-white solid which was used directly in the next reaction. 1H NMR (300 MHz, CDCl3): 613.10 (br s, 2H) 7.45 (dd, J=5.2, 8.9 Hz, 2H), 7.03 (dd, J=2.3, 9.8 Hz, 2H), 6.85 (m, 2H), 5.35 (m, 2H), 3.71 (m, 2H), 3.18-3.35 (m, 4H), 2.90-3.14 (m, 4H), 2.56 (m, 2H), 2.00-2.10 (m, 2H), 2.04 (s, 6H), 1.80-1.92 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3): δ171.3, 161.7, 158.6, 136.1, 135.9, 130.5, 130.4, 125.4, 119.1, 118.9, 109.6, 108.0, 107.6, 97.6, 97.5, 75.1, 57.7, 51.6, 38.7, 32.8, 21.6 ppm. Mass spectrum (ESI), m/z 550.9 [(M)+; calcd for C30H32F2N4O4: 550.6].
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cn(CCF)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CCF)CC1
Yield: 56.9 %

Procedure:
A mixture of 1-(2-fluoroethyl)-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.72 g) (2.5 millimole), N-methylpiperazine (1.25 g) (12.5 millimole) and 2 ml pyridine was heated at 135°-145° C. for 10 hours. After cooling, the mixture was evaporated under vacuum. The residue was acidified with acetic acid. The undissolved matter was filtered off. The filtrate was neutralized with an aqueous solution of caustic soda. The presipitate was filtered, washed and dried and recrystallized from a mixture of DMF and ethanol. 0.50 g (57%) of 1-(2-fluoroethyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N#N.Cl[C:18](Cl)(Cl)[C:19](Cl)=[O:20].[NH4+].[Cl-]>COCCOC.C(OC)(C)(C)C>[O:20]=[C:19]1[CH2:18][C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:1]1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C2
Temperature: 15 °C
Yield: 15 %

Procedure:
To a flame-dried RB flask with tert-butyl 4-methylenepiperidine-1-carboxylate (2.96 g, 15 mmol, 1.0 equiv) and Zn/Cu couple (6.54 g, 172.5 mmol, 11.5 equiv) under vacuum, t-BuOMe (60 mL) was charged and refilled the flask with N2 balloon. To the mixture thus obtained stirred at 15° C., a solution of 2,2,2-trichloroacetyl chloride in DME (20 mL) was added dropwise. The mixture was stirred at room temperature overnight after addition. To the reaction mixture stirred in an external ice-bath, a saturated solution of NH4Cl (60 mL) was added slowly and carefully (especially the first few drops). After addition, the mixture was stirred at room temperature for 4 h, filtered to remove the solid. The phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated to give the residue which was purified by CombiFlash (40 g silica gel column, EtOAc/Hexane: 0-40%) to afford 619 mg (15%) of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15]C)=[O:14])[CH2:10][CH2:9][N:8]2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.[Li+].[OH-].CO.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10][CH2:9][N:8]2[C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(Cl)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
Dimethyl 2-(4-chlorobenzyl)piperidine-1,4-dicarboxylate (4.74 g, 14.55 mmol) was dissolved in tetrahydrofuran (15 mL) followed by addition of LiOH (0.430 g, 17.97 mmol), MeOH (10 mL) and water (10 mL). The reaction mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was taken up in water. The pH was adjusted to <2 by addition of 2 M HCl. The product was poorly soluble and attempts to extract the aqueous phase with DCM and ethyl acetate failed. Instead the mixture was concentrated and then filtered, washed with water and dried to give a yellow solid material. The water phase did contain some product and was extracted with DCM (×3) and dried with a phase separator to give about 500 mg. Crude 2-(4-chlorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.27 g, quant.) was isolated. MS m/z 312, 314 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([O:22]C1C=CC=CC=1)=O.[CH3:29][N:30]([CH3:32])[NH2:31]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([NH:31][N:30]([CH3:32])[CH3:29])=[O:22]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: CN(C)N
Product: CN(C)NC(=O)c1c(Nc2ccc(I)cc2F)n(C)c(=O)n(C)c1=O

Procedure:
Example 45 was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and 1,1-dimethylhydrazine. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.0 Hz, 1H) 7.58 (d, J=8.0 Hz, 1H) 6.99 (t, J=8.0 Hz, 1H) 3.33 (s, 3H) 3.08 (s, 3H) 2.60 (s, 6H). [M+H] calc'd for C15H17FIN5O3, 462; found, 462.
Reaction SMILES: [NH2:1][C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)N.Br>>[NH2:1][CH:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: NC(N)(c1cccnc1)C1CCOCC1
Agent: Br
Product: NC(c1cccnc1)C1CCOCC1

Procedure:
Treatment of 1-amino-1-(3-pyridyl)-1-(4-tetrahydropyranyl)-methaneamine (576 mg, 3 mmol) with hydrobromic acid, as described for the synthesis of the 1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptanes resulted in formation of the product, as a dark brown oil which was purified by column chromatography (15% methanol in chloroform), followed by distillation (90° C. at 0.005 mm Hg) under reduced pressure to obtain the product as a colorless oil (260 mg, 51% from 1-amino-1-(3-pyridyl)-1-(4-tetrahydropyranyl)-methane.
Reaction SMILES: [FH:1].F.F.C(N(CC)CC)C.C(N(CC)CC)C.[F:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][O:24][C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[C:30]([C:35](O)([CH3:37])[CH3:36])[CH:31]=[N:32]3)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][O:24][C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[C:30]([C:35]([F:1])([CH3:37])[CH3:36])[CH:31]=[N:32]3)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(F)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Temperature: 0 °C
Yield: 30.6 %

Procedure:
XtalFluor® (66.19 mg, 0.29 mmol) was transferred to a flask and put under nitrogen, then DCM (2 mL) was added via syringe. The reaction was cooled to 0° C. in an ice bath then triethylamine trihydrofluoride (62.76 μl, 0.39 mmol) and triethylamine (26.7 μL, 0.19 mmol) were added via syringe. The reaction was stirred until all solids dissolved completely then was cooled to −78° C. in a dry ice/acetone bath. A solution of 2-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)propan-2-ol (Example 27, 60 mg, 0.19 mmol) in DCM (1 mL) was added via syringe then the reaction was warmed to 0° C. and allowed to stir for 1 hour. Upon completion, a solution of NaHCO3 (sat aq.) and EtOAc was added. The combined organics were separated and washed with a 50% aq. bleach solution. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification (FCC, SiO2, 0-25%, EtOAc/Hexanes), and a second purification with preparative HPLC (Shimadzu SCL-10 VP, ACN/H2O, 25-90% (0.1% TFA)) afforded the title compound as a pure solid (18.2 mg, 22%). 1H NMR (400 MHz, CDCl3) δ 9.08 (d, J=1.8 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.53 (dd, J=5.4, 8.4 Hz, 2H), 7.43 (d, J=9.0 Hz, 1H), 7.29 (s, 1H), 7.12 (t, J=8.7 Hz, 2H), 5.35 (s, 2H), 1.99-1.63 (m, 6H). [M+H]=314.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][N:7]([CH3:9])[CH3:8].C([Li])CCC.[CH3:18][S:19]SC.O>C1COCC1.C(OCC)C>[CH3:18][S:19][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[CH:10][C:5]=1[CH2:6][N:7]([CH3:9])[CH3:8]
Reactant: COc1cccc(CN(C)C)c1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CN(C)C)c1SC
Temperature: 0 °C
Yield: 57.5 %

Procedure:
Under a nitrogen atmosphere, 3-methoxy-N,N-dimethylbenzylamine (2.00 g, 12.1 mmol) was dissolved in anhydrous THF (20 mL) and cooled to 0° C. in an ice bath. 2.5M n-butyl lithium in hexanes (5.3 mL, 13.3 mmol) was added slowly, maintaining the temperature to below 5° C. The reaction was stirred at 0° C. for 2 b, then dimethyldisulfide (1.59 g, 13 mmol) was slowly added over 90 min, maintaining the temperature to below 5° C. The reaction mixture was stirred for 17 h, during which time the temperature was allowed to reach room temperature. Water (20 mL) and diethyl ether (30 mL) were added and the organic layer was separated and dried with MgSO4. After filtration, the crude solution was dissolved in ethyl acetate and absorbed in vacuo onto silica gel (1.5 g). This material was chromatographed on an ISCO CombiFlash Chromatography System to yield (2-methylsulfanyl-3-methoxybenzyl)-dimethyl-amine as a yellow oil (1.47 g, 57%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[N:3][CH:2]=1.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccncn1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccncn1)N1CCN(c2nc(-c3ccccc3)cs2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl pyrimidin-4-ylcarbamate (200 mg, 0.739 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (181 mg, 0.739 mmol), diisopropylethylamine (0.258 ml, 1.48 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (135 mg, 49.8%) as a solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:21][N:22]1[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:24]=[CH:23]1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:27]([C:25]2[N:24]=[CH:23][N:22]([CH3:21])[CH:26]=2)(=[O:29])=[O:28])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 1-methylimidazole-4-sulfonyl chloride (524 mg). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(1-methylimidazole-4-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (730 mg).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=2[C:26]#[N:27])=[CH:20][CH:19]=1>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=3[C:26]#[N:27])=[CH:20][CH:19]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccc(Cl)cc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2cc(Cl)ccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
522 g of 2-n-butylbenzimidazole was dissolved in 10 ml of dimethylformamide and dropwise added to 130 g of sodium hydride. The mixture was stirred at room temperature for 30 min, and 920 mg of 2-(4-bromomethylphenyl)-4-chlorobenzonitrile dissolved in 10 ml of dimethylformamide was dropwise added thereto. The mixture was stirred at room temperature for 10 min, and the reaction mixture was filtered. The filtrate was concentrated and water and ethyl acetate were added to the residue. The organic phase was separated, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by column chromatography (chloroform:ethanol=98:2) (yield: 1.12 g).
Reaction SMILES: N1(O[C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:24]=3[N:25]=[CH:26][N:27]=2)[C@@H:16]2[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[CH2:17]2)C2C=CC=CC=2N=N1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[C@@H:16]1([N:15]2[CH:14]=[N:13][C:12]3[C:24]2=[N:25][CH:26]=[N:27][C:11]=3[N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[CH2:17]1
Reactant: C1COCCN1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: OC[C@H]1O[C@@H](n2cnc3c(N4CCOCC4)ncnc32)C[C@@H]1O
Yield: 51.7 %

Procedure:
As described for the synthesis of 6-(morpholin-1-yl)-9-[2-deoxy-3,5-bis-O-(tert-butyldimethylsilyl)-β-D-erythro-pentofuranosyl]purine, this morpholino derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-2′-deoxyinosine (28) (36.9 mg, 0.100 mmol), and morpholine (17.5 μL, 0.200 mmol) in the presence of Cs2CO3 (65.2 mg, 0.200 mmol) in dry DME (1.0 mL) at room temperature over 1 h. Chromatographic purification (SiO2, elution with 5% MeOH in CH2Cl2) afforded 16.6 mg (52% yield) of the title compound as a clear gum. Rf (10% MeOH in CH2Cl2)=0.34. 1H NMR (500 MHz, CDCl3): δ 8.26 (s, 1H, Ar—H), 7.77 (s, 1H, Ar—H), 6.88 (br, 1H, OH, CD3OD exchangeable), 6.30 (dd, 1H, H-1′, J=9.8, 5.4), 4.77 (d, 1H, H-3′, J=4.8), 4.30 (br, 4H, 2CH2), 4.21 (br s, 1H, H-4′), 3.96 (dd, 1H, H-5′, J=12.7, 1.2), 3.81 (t, 4H, 2CH2, J=4.9), 3.77 (br d, 1H, H-5′, J=13.2), 3.10 (ddd, 1H, H-2′, J=13.7, 9.3, 4.9), 2.65 (br, 1H, OH, CD3OD exchangeable), 2.26 (dd, 1H, H-2′, J=13.7, 5.6). 13C NMR (126 MHz, CDCl3): δ 154.1, 151.6, 149.4, 138.3, 121.7, 89.7, 87.8, 73.6, 67.0, 63.5, 45.6, 40.5.
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:24])[CH:10]2[NH:14][C:15](=[O:23])[CH2:16][C:17]2[S:18][C:19](=[O:22])[S:20][CH:21]=2)[C:7]=1[C:25]([OH:27])=[O:26])(=O)C.[CH3:28][C:29]1[CH2:33][S:32][C:31](=[S:34])[N:30]=1.Cl.C(OC(C)C)(C)C>O.C(=O)(O)[O-].[Na+].CO>[C:25]([C:7]1[N:8]2[CH:11]([S:12][CH2:13][C:6]=1[CH2:5][S:34][C:31]1[S:32][CH:33]=[C:29]([CH3:28])[N:30]=1)[CH:10]([NH:14][C:15](=[O:23])[CH2:16][C:17]1[S:18][C:19](=[O:22])[S:20][CH:21]=1)[C:9]2=[O:24])([OH:27])=[O:26]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Reactant: CC1=NC(=S)SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)OC(C)C
Solvent: O
Product: Cc1csc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4csc(=O)s4)C3SC2)n1
Temperature: 60 °C
Yield: 22.3 %

Procedure:
3-Acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene (7.7 g.) is dissolved in distilled water (100 cc.) and sodium bicarbonate (1.64 g.). A solution of 4-methyl-2-thioxo-1,3-thiazoline (2.76 g.) in distilled water (75 cc.) and sodium bicarbonate (1.64 g.) is added and the resulting solution is heated to 60° C. for 6 hours. After cooling, it is acidified to pH 5.5 by adding 4 N hydrochloric acid and then extracted with ethyl acetate (100 cc.), which is discarded. The acidification is continued to pH 2 in the presence of ethyl acetate (300 cc.). After decanting the organic phase, the aqueous phase is extracted twice with ethyl acetate (a total of 200 cc.). The organic extracts are washed twice with water (200 cc.), dried over magnesium sulphate, treated with decolourising charcoal and then filtered and concentrated to dryness under reduced pressure (20 mm Hg). The residue obtained is dissolved in methanol (30 cc.) and this solution is then added to isopropyl ether (200 cc.). A product precipitates and is isolated by filtration to give 2-carboxy-3-[(4-methyl-1,3-thiazol-2-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (2 g.).
Reaction SMILES: [C:1]([C@@H:4]1[CH:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)(O)=[O:2].[NH3:25]>C1(C)C=CC=CC=1.O=S(Cl)Cl.C1COCC1>[C:1]([C@@H:4]1[CH:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)(=[O:2])[NH2:25]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C(=O)O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@]12CCC(=O)CC1[C@@H](C(N)=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 85 °C
Reaction time: 5.5 h

Procedure:
To a stirred suspension of 6α-carboxyandrostane-3,17-dione (1.20 g) in dry toluene (12 mL), SOCl2 (1.2 mL) was added. After stirring 5.5 h at 85° C. the solution was cooled at 0° C. and 2M NH3 solution in THF (6 mL) was added. After stirring overnight at room temperature, the mixture was evaporated to dryness. The residue was treated with CH2Cl2 and H2O and extracted with CH2Cl2. The combined organic extracts were washed with 10% K2CO3 solution, brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone 50/50) to give the title compound II-af (720 mg, 60%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 7.27 (1H, bs), 6.78 (1H, bs), 2.50-0.72 (21H, m), 1.00 (3H, s), 0.80 (3H, s).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:5]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH:2]([CH:3]1[CH:5]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:1]
Reactant: CCOC(=O)C1C(CO)C1CCc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCOC(=O)C1C(C=O)C1CCc1ccccc1
Reaction time: 0.08 h
Yield: 61.8 %

Procedure:
To a solution of ethyl (1SR,2SR,3RS) 2-hydroxymethyl-3-(2′-phenylethyl)cyclopropanecarboxylate (1.15 g, 4.6 mmol) in CH2Cl2 (40 mL) at room temperature and under argon, a molecular sieve (4 Å) (2.2 g) was added. After stirring 5 minutes, NMO (0.54 g, 4.6 mmol) and TPAP (0.03 g, 0.09 mmol) were added and the mixture was stirred overnight. Then the reaction mixture was filtered through celite and the solvent was removed to dryness. After purification of the crude by column chromatography using AcOEt/Hexane 1:6 as eluent, 0.7 g (63% yield) of ethyl (1SR,2SR,3RS) 2-formyl-3-(2′-phenylethyl)cyclopropanecarboxylate was obtained as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CO[C:21](OC)([CH3:23])[CH3:22].[BH4-].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:22][CH:21]([NH:1][C:2]1[S:3][C:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:23]
Reactant: CCOC(=O)c1cc(Cc2ccccc2)sc1N
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cc2ccccc2)sc1NC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-amino-5-(phenylmethyl)thiophene-3-carboxylic acid, ethyl ester (2.61 g) and 4-methylbenzenesulfonic acid (30 mg) in dry toluene (50 ml) was added 2,2-dimethoxypropane. The solution was heated to reflux for 5 hours and then allowed to cool to ambient temperature. A solution of sodium borohydride (800 mg) in ethanol (100 ml) was added to the solution and the mixture was stirred at room temperature under nitrogen for 24 hours. The mixture was diluted with water and then extracted thrice with ethyl acetate. The combined organic extracts were washed with brine and then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give an oil. The residue was purified by column chromatography over silica, eluting with diethyl ether:isohexane (1:19) to give the subtitle compound (550 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:10][CH2:9]1
Reactant: O=C1CCC(Oc2ccccn2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(Oc3ccccn3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(pyridin-2-yloxy)-cyclohexanone (as prepared in Step A) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in the previous step) using the procedure described in Step D of Example 1.