Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:28])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21](OS(C)(=O)=O)[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>CN(C)C=O>[C:29]([S:31][CH:21]1[CH2:20][N:19]([C:16]2[S:17][CH:18]=[C:14]([C:12](=[O:13])[N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:28])[N:15]=2)[CH2:22]1)(=[O:32])[CH3:30]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N(C)CCO[Si](C)(C)C(C)(C)C)cs2)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
To a solution of 1-(4-{N-[2-(t-butyldimethylsilyloxy)ethyl]-N-methyl-carbamoyl}-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (516 mg, 1.14 mmol) (obtained as described in Reference Example 40(5)) in dimethylformamide (15 ml) was added potassium thioacetate (815 mg, 7.14 mmol) at room temperature. The mixture was stirred in an oil bath (90° C.) for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:2) as the eluant to afford 3-acetylthio-1-(4-{N-[2-(t-butyldimethylsilyloxy)ethyl]-N-methyl-carbamoyl}-1,3-thiazol-2-yl)azetidine (279 mg, yield 57%) as a pale brown solid.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:26])[NH:18][C:19]1[S:20][CH:21]=[C:22]([S:24][CH3:25])[N:23]=1)(=[O:9])[CH3:8]>O.CO>[C:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:26])[NH:18][C:19]1[S:20][CH:21]=[C:22]([S:24]([CH3:25])=[O:1])[N:23]=1)(=[O:9])[CH3:8]
Reactant: CSc1csc(NC(=O)c2ccccc2OC(C)=O)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)Nc1nc(S(C)=O)cs1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 100 %

Procedure:
A solution of Oxone® (2.71 g, 4.44 mmol) dissolved in a minimum amount of water (15.0 mL) was added to a cold solution (0° C.) of 509 (0.514 g, 1.47 mmol) dissolved in a minimum amount of methanol (200 mL). On addition of the Oxone® solution a white solid precipitated. Additional methanol (100 mL) was added to the reaction. After stirring 25 min at 0° C., a saturated aqueous solution of Na2S2O3 was added to the reaction. The reaction was concentrated to remove excess methanol. The aqueous residue was washed four times with dichloromethane. The combined dichloromethane layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give crude 1 (0.66 g, >100%) as a white foam. This residue was dissolved in ethyl acetate and loaded onto a 90 g silica gel column that had been pre-equilibrated with ethyl acetate. The column was eluted with ethyl acetate. Like fractions of pure product were combined and concentrated in vacuo. The residue was stirred with ether and evaporated in vacuo to give 1 (0.288 g, 60%) as a white solid. 1H-NMR showed clean desired product contaminated with traces of residual dichloromethane and ethyl acetate. HPLC analysis indicated the product to be 95% pure (tR=5.01 min, Condition C) contaminated with 3% of 2 (tR=5.33 min, Condition C).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]([CH3:29])[C:20]3[O:24][C:23]([C:25](O)=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].C(Cl)CCl.Cl.C[O:40][C:41](=[O:44])[CH2:42][NH2:43]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:33][C:2]([CH3:1])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]([CH3:29])[C:20]3[O:24][C:23]([C:25]([NH:43][CH2:42][C:41]([OH:40])=[O:44])=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:8][C:7]=1[CH3:30]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)O)cc2c1
Reactant: COC(=O)CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)NCC(=O)O)cc2c1
Yield: 97.4 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-7-methyl-benzofuran-2-carboxylic acid (360 mg, 0.799 mmol) in CH2Cl2 (10 ml) and DMAP (293 mg, 2.40 mmol), EDC (230 mg, 1.20 mmol), and glycine methyl ester hydrochloride (150 mg, 1.20 mmol) are reacted and hydrolyzed analogous to Example 7 to yield title compound (395 mg, 97%).
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[CH2:8]([N:10]([CH3:40])[C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:29]2[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]2)=[CH:13][CH:12]=1)[CH3:9].CNC>>[CH2:38]([S:35]([N:32]1[CH2:33][CH2:34][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:14]4[CH:15]=[N:16][C:11]([N:10]5[CH2:40][CH2:3][O:4][CH2:9][CH2:8]5)=[CH:12][CH:13]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:30][CH2:31]1)(=[O:37])=[O:36])[CH3:39]
Reactant: CCN(C)c1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cn1
Reactant: O=C(O)C(F)(F)F
Agent: CNC
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(N5CCOCC5)nc4)cc23)CC1
Yield: 69.5 %

Procedure:
The title compound was prepared according to the general procedure of 5-{6-[ethyl(methyl)amino]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting morpholine (1 mL) for dimethylamine to afford 40.1 mg of the title compound (69.5%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2.[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18]OS(C)(=O)=O>>[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Reactant: O=C1OCCc2cc(O)ccc21
Product: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21

Procedure:
6-Hydroxy-isochroman-1-one was reacted with Methanesulfonic acid (S)-1-(tetrahydro-furan-2-yl)methyl ester by method K1. The product with the molecular weight of 248.28 (C14H28FN3O3) was obtained in this way; MS (ESI): 249 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[F:63][C:64]1[CH:70]=[C:69]([S:71]([CH3:74])(=[O:73])=[O:72])[CH:68]=[CH:67][C:65]=1[NH2:66]>>[F:63][C:64]1[CH:70]=[C:69]([S:71]([CH3:74])(=[O:72])=[O:73])[CH:68]=[CH:67][C:65]=1[NH:66][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: CS(=O)(=O)c1ccc(N)c(F)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(S(C)(=O)=O)cc2F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.36 g, 0.62 mmol), was reacted with diisopropylethylamine (0.64 g, 5 mmol), diphenylphosphinic chloride (0.59 g, 2.5 mmol), then reacted with 2-fluoro-4-(methylsulfonyl)aniline (Matrix) (0.12 g, 0.62 mmol) at 80° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-fluoro-4-methanesulfonyl-phenyl)-amide as a off white solid (Yield 20 mg, 5%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH2:5][N:6]=[C:7]=[S:8].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:28]2[C:29]3[CH2:35][CH2:34][NH:33][CH2:32][C:30]=3[S:31][C:27]=2[N:26]2[C:36]([CH3:39])=[N:37][N:38]=[C:25]2[CH2:24][N:23]=1>ClCCl>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:28]2[C:29]3[CH2:35][CH2:34][N:33]([C:7](=[S:8])[NH:6][CH2:5][C:4]4[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=4[C:2]([F:13])([F:1])[F:14])[CH2:32][C:30]=3[S:31][C:27]=2[N:26]2[C:36]([CH3:39])=[N:37][N:38]=[C:25]2[CH2:24][N:23]=1
Reactant: FC(F)(F)c1ccccc1CN=C=S
Reactant: Cc1nnc2n1-c1sc3c(c1C(c1ccccc1Cl)=NC2)CCNC3
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc3c(c1C(c1ccccc1Cl)=NC2)CCN(C(=S)NCc1ccccc1C(F)(F)F)C3

Procedure:
A mixture containing 2-trifluoromethylbenzylisothiocyanate (1 g, 0.0046 mol) and 6-(2-chlorophenyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4′,3′;4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (1.22 g, 0.0033 mol) in 20 ml of dichloromethane is agitated at a temperature close to 20° C. for 1 hour. The reaction mixture is evaporated to dryness. 40 ml of ethyl acetate is added to the residual oil. After separation of the insoluble part, the solvent is evaporated off. 40 ml of isopropyl ether is added until precipitation of the product then filtration on frit and washing with isopropyl ether. The solid obtained (1.2 g, 63%) is dried and a beige powder is obtained. Melting point: 178–184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:14]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C1(C)C=CC=CC=1.[C:45](Cl)(=[O:50])[CH2:46][CH:47]([CH3:49])[CH3:48]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:45](=[O:50])[CH2:46][CH:47]([CH3:49])[CH3:48])[C:9]2[CH:10]=[C:11]([CH:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)CC(=O)Cl
Reactant: CC(C)CC(C(=O)O)c1cc(Nc2ccc(Cl)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CC(=O)N(c1ccc(Cl)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(CC(C)C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.1 %

Procedure:
To a solution of 2-[5-(4-chloro-phenylamino)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid (51.1 mg, 0.11 mmol), sodium acetate 40 mg, 1.1 mmol) and toluene (0.5 mL) was added isovaleryl chloride (60 μL, 0.55 mmol) and the resulting mixture was stirred at RT for 48 hr. The mixture was treated with water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried with MgSO4, filtered and the solvent was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (gradient 0% to 30% EtOAc/heptane) to afford 16.3 mg (27%) of the title compound as a solid. 1H-NMR (CDCl3; 300 MHz): δ 7.6-7.7 (m, 4H), 6.98-7.45 (m, 7H), 3.7 (m, 1H), 2.2 (m, 2H), 2.0 (m, 1H), 1.7 (m, 1H), 1.5 (m, 1H), 1.25 (bs, 1H), 0.85-1.0 (m, 12H). Mass spectrum (ESI, m/z): Calcd. for C30H31ClF3NO3, 546.03 (M+H), found 548.26, 546.29.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@@H:12]2[CH2:16][C@H:15]([S:17][C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25]CC3C=CC([N+]([O-])=O)=CC=3)=[O:24])[CH2:14][N:13]2[CH3:43])=[O:11])[CH2:6][CH2:5]1.O1CCCC1.[ClH:49]>O>[ClH:49].[OH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]([C@@H:12]2[CH2:16][C@H:15]([S:17][C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([OH:25])=[O:24])[CH2:14][N:13]2[CH3:43])=[O:11])[CH2:8][CH2:9]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(CCO)CC4)N(C)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CCN(CCO)CC4)N(C)C3)[C@H](C)[C@H]12

Procedure:
A solution of 700 mg of 4-nitrobenzyl (1R,5S,6S)-2-{(2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-1-methylpyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] in 60 ml of a 1:1 by volume mixture of tetrahydrofuran and water was mixed with 1.15 ml of 1N aqueous hydrochloric acid, and the mixture was hydrogented by bubbling hydrogen through it at room temperature for 2 hours in the presence of 1000 mg of 10% w/w palladium-on-charcoal. At the end of this time, the catalyst was removed by filtration, and the filtrate was extracted with diethyl ether. The remaining aqueous layer was concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through a Lobar column (Merck, LiChroprep RP-8, size B). The column was eluted with 1.5% v/v aqueous methanol and those fractions containing the title compound were combined, concentrated by evaporation under reduced pressure and lyophilized, to give 300 mg of the title compound as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([F:17])[CH:16]=2)[CH:13]([NH:18][C:19]([C:21]2([NH2:24])[CH2:23][CH2:22]2)=[O:20])[CH2:12][CH2:11]3)[CH:7]=1.[CH3:32][O:33][C:34]1[CH:38]=[C:37]([C:39](O)=[O:40])[O:36][N:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([F:17])[CH:16]=2)[CH:13]([NH:18][C:19]([C:21]2([NH:24][C:39]([C:37]4[O:36][N:35]=[C:34]([O:33][CH3:32])[CH:38]=4)=[O:40])[CH2:23][CH2:22]2)=[O:20])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cc(F)c3c(c2)CCC3NC(=O)C2(N)CC2)no1
Reactant: COc1cc(C(=O)O)on1
Product: COc1cc(C(=O)NC2(C(=O)NC3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)cc(F)c43)CC2)on1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro-indan-1-yl}-amide (example 32) has been coupled with 3-methoxy-isoxazole-5-carboxylic acid to yield the title compound as light red oil. MS: 570.1 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]1[C:19]2[C:14](=[CH:15][C:16]([N:20]=[C:21]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:22]=[CH:23]S(C3C=CC=CC=3)(=O)=O)=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.COC(C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:23]=[CH:22][C:21](=[N:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[CH2:11][CH2:12][CH2:13]3)[O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(C=CC(=Nc1ccc2c(c1)CCC2)Oc1ccccc1)c1ccccc1
Reactant: Fc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: Fc1ccc(SC=CC(=Nc2ccc3c(c2)CCC3)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
To a solution of 4-fluorothiophenol (0.22 g) in DMF (6 mL) was added 60% sodium hydride (84 mg), and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The reaction mixture was added to a solution of phenyl N-(5-indanyl)-3-(phenylsulfonyl)acrylimidate (0.65 g) in anhydrous DMF (3 mL) under ice-cooling. The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added tert-butyl methyl ether (50 mL), which was washed with a 1N aqueous sodium hydroxide solution, water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was isolated and purified by medium pressure preparative liquid chromatography (Yamazen SI-40B, hexane:ethyl acetate=19:1) to obtain phenyl 3-(4-fluorophenylthio)-N-(5-indanyl)acrylimidate (0.16 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:13][N+:14]([O-])=O)[N:7]=[N:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]>C(O)(=O)C.O.[Zn]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:13][NH2:14])[N:7]=[N:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1cc(N[N+](=O)[O-])nnc1OCC
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1cc(NN)nnc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
N-(5,6-Diethoxypyridazin-3-yl)-N-nitroamine (W4.120; 114 mg) was dissolved in acetic acid (5 ml) and added dropwise while cooling with ice and stirring at between 10 and 20° C. to a mixture of zinc (130 mg) in water (3 ml). Thereafter, the ice bath was removed and the mixture was stirred at RT for 1 h. Then the mixture was alkalized with 10 N sodium hydroxide solution, the aqueous phase was extracted three times with DCM, and the combined DCM phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (met. A). The clean, product-containing fractions were each combined, freed of the ACN, basified with saturated potassium carbonate solution and then extracted three times with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 50 mg of the title compound were obtained. LC-MS rt: 0.37 min
Reaction SMILES: [OH:1][C:2]1([CH2:16][C:17](O)=O)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:20][C:21]1[C:34]([Cl:35])=[CH:33][C:24]2[NH:25][C:26]([CH2:28][CH2:29][CH2:30][NH:31][CH3:32])=[N:27][C:23]=2[CH:22]=1>>[Cl:35][C:34]1[C:21]([Cl:20])=[CH:22][C:23]2[NH:27][C:26]([CH2:28][CH2:29][CH2:30][N:31]([CH3:32])[CH2:17][CH2:16][C:2]3([OH:1])[CH2:7][CH:6]4[CH2:8][CH2:9][CH:3]3[CH:4]=[C:5]4[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:25][C:24]=2[CH:33]=1
Reactant: O=C(O)CC1(O)CC2CCC1C=C2c1ccccc1
Reactant: CNCCCc1nc2cc(Cl)c(Cl)cc2[nH]1
Product: CN(CCCc1nc2cc(Cl)c(Cl)cc2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1

Procedure:
Prepared according to procedures P2.2 to P2.3 in Example 21 using rac-(1R*,2R*,4R*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid and [3-(5,6-dichloro-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=2)=[CH:4][C:5]([C@H:10]2[C@H:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:14]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:13]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:12]([CH2:40][O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:11]2)=[C:6]([CH:9]=1)[CH:7]=[O:8].OO.Cl([O-])(=O)(=O)=[O:61].[Na+]>CC(O)(C)C.O>[Cl:1][C:2]1[C:3]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[CH:4][C:5]([C@H:10]2[C@H:15]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@@H:14]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:13]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:12]([CH2:40][O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:11]2)=[C:6]([CH:9]=1)[C:7]([OH:61])=[O:8]
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(C=O)cc2Cl)cc1
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(C(=O)O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 5-chloro-4-(4-ethylbenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzaldehyde (0.826 g, 1.1 mmol) in t-BuOH/water (3:1, 17 mL) was added hydrogen peroxide (30%, 5.29 mL, 46.7 mmol) and sodium perchlorate (0.14 g, 1.1 mmol), and the solution was stirred overnight at RT. The volatiles were removed under reduced pressure, and the residue was quenched with water. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with water and then with brine, and then dried over anhydrous sodium sulfate. After removal of the volatiles, 0.802 g of crude solid product was obtained. MS ESI− (m/z): 841 (M+45)−.
Reaction SMILES: [Cl:1][C:2]1[C:20]([OH:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]1=[O:16].C1C(=O)N([Br:30])C(=O)C1>C(O)(=O)C>[Br:30][C:19]1[CH:18]=[C:17]([Cl:22])[C:3]([CH2:4][CH:5]2[CH2:9][CH2:8][N:7]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)[C:6]2=[O:16])=[C:2]([Cl:1])[C:20]=1[OH:21]
Reactant: O=C1C(Cc2c(Cl)ccc(O)c2Cl)CCN1C1CCCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: O=C1C(Cc2c(Cl)cc(Br)c(O)c2Cl)CCN1C1CCCCC1
Yield: 84.9 %

Procedure:
Place 3-(2,6-dichloro-3-hydroxybenzyl)-1-cyclohexylpyrrolidin-2-one (1.116 g, 3.26 mmol) in acetic acid (5 mL). Add NBS (0.609 g, 3.42 mmol) and stir at room temperature for 2 hours. Pour reaction mixture onto water, filter, and dry to give 1.165 g (85%) of the title compound. Mass spectrum (apci) m/z=422.1 (M+H).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[O:35])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([C:21]2[N:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[OH:35])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccnnc1
Reactant: O=CCCCCCCc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(CCCCCCc1ccccc1)c1cccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
2,2,6,6-Tetramethylpiperidine (1.54 mL) was dissolved in anhydrous THF (60 mL) and treated dropwise with 2.0 M n-BuLi (4 equiv) at −40° C. The reaction mixture was stirred at 0° C. for 0.5 h, cooled to −78° C. and treated with a solution of pyridazine (165 μL, 2.26 mmol) in THF (4 mL) immediately followed by a solution of 7-phenylheptanal (435 mg, 2.29 mmol) in THF (2 mL). The reaction mixture was stirred at −78° C. for 1 h before being quenched by the addition of 1 N HCl/EtOH/THF (2/9/9, 40 mL). The reaction mixture was diluted with EtOAc, and washed with H2O, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography (SiO2, 3×15 cm, 1% MeOH—CH2Cl2) afforded the alcohol (135 mg, 22%) as colorless oil: 1H NMR (CDCl3, 500 MHz) δ 9.12 (dd, 1H, J=1.8, 4.7 Hz), 7.49 (m, 2H), 7.26 (m, 2H), 7.17 (m, 3H), 4.97 (td, 1H, J=4.9, 8.0 Hz), 3.60 (d, 1H(—OH), J=5.4 Hz), 2.58 (t, 2H, J=7.7 Hz), 1.88 (m, 1H), 1.77 (m, 1H), 1.43 (m, 2H), 1.34 (m, 6H).