Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15]O)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15][S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(NCCCO)c(=O)c1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOc1c(NCCCS(=O)(=O)c2ccccc2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
A solution of 1-butoxy-2-(3-hydroxypropylamino)-1-cyclobutene-3,4-dione [prepared in Example 7] (1.14 g, 5.0 mmol) and pyridine (0.65 mL, 8.0 mmol) in 6.0 mL of dichloromethane cooled to 0° C. was treated dropwise with benzenesulfonyl chloride (0.65 mL, 5.1 mmol). The mixture was stirred at ambient temperature for 3 hours, then washed with water (4 times), dried and evaporated under reduced pressure to give 1.53 g (83% yield) of title compound which was used without purification in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH:12]([OH:15])S[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].I([O-])(=O)(=O)=[O:17].[Na+]>CO.O.[Ru](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH:12]([OH:15])[O:17][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1C(O)SCN1c1ccc(Cl)c(Cl)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C(O)OCN1c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 21 %

Procedure:
A stirred solution of 3-(3,4-dichlorophenyl)-5-hydroxythiazolidin4-one (264 mg, prepared as in Example 1 of WO 94/13652) in methanol (5 ml) was treated with a solution of sodium periodate (852 mg) in water (10 ml). More methanol (5 ml) was added to redissolve the cloudy precipitate which formed. Ruthenium trichioride (10 mg) was added, whereupon the solution turned brown, became warm and a precipitate slowly formed. The resultant slurry was stirred for 2 hours, then water (30 ml) was added and the mixture extracted with ethyl acetate (3×20 ml). The combined ethyl acetate extracts were washed with saturated aqueous sodium sulfite solution (2×20 ml), water (3×20 ml) and brine (20 ml), then dried (MgSO4). Evaporation of the solvent under reduced pressure gave a yellow oil, which was purified by silica-gel chromatography, eluting with ethyl acetate/hexane mixtures, then by high-pressure silica-gel chromatography, eluting with 60% ethyl acetate/hexane, to give the title compound as a white solid (52 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:15]1[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:15]3[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:16]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccccc2)nc(Cl)c1C
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)nc(N2CCN(c3ccc(O)cc3)CC2)c1C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A solution of 1.89 (10.6 mmol) of 1-(4-hydroxyphenyl)piperazine and 2.19 g (10 mmol) of 4-chloro-5,6-dimethyl-2-phenylpyrimidine in 30 ml of absolute N,N-dimethylformamide (DMF) was warmed to 80° C., and 234 mg of powdered K2CO3 were added at 80° C., with stirring, under a nitrogen atmosphere in each case after 10 minutes, after a further 25 minutes and after a further 60 minutes (total addition of 702 mg (5.08 mmol) of K2CO3). The mixture was stirred for a further 6 hours at 90° C., the DMF was substantially removed by distillation in an oil-pump vacuum in a rotary evaporator, the residue remaining was taken up in CH2Cl2 /water, and the pH was adjusted to 7-8 using dilute hydrochloric acid. After thoroughly mixing and separating the phases, the aqueous phase was extracted a further twice with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The crystalline residue (3.6 g) was chromatographed on a silica gel S/CH2Cl2 column (diameter 2.0 cm, height 38 cm) by elution with CH2Cl2 and CH2Cl2 /C2H5OH mixtures with increasing C2H5OH content (to a maximum of 10% by volume of C2H5OH). The substance was drawn onto the column using 60 ml of a CH2Cl2 /tetra-hydrofuran 2:1 mixture. The eluted, not completely pure, crystalline substance was purified by boiling with a little CH2Cl2 and filtering off under suction. 2.22 g (=61.5% yield) of pure 1-(4-hydroxyphenyl)-4-(5,6-dimethyl-2-phenylpyrimidin-4-yl)piperazine, melting point 202°-03° C., were obtained;
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:15][S:16]([O:2][C@H:3]1[CH2:7][CH2:6][N:5]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:4]1)(=[O:18])=[O:17]
Reactant: O[C@H]1CCNC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 62.9 %

Procedure:
The crude (S)-3-hydroxyl-pyrrolidine hydrochloride 11b (124 mg, 1 mmol) was dissolved in 15 mL of dichloromethane, followed by addition of triethylamine (303 mg, 3 mmol). The reaction solution was cooled down to 0° C., followed by addition of methanesulfonyl chloride (264 mg, 2.30 mmol), then warmed up to room temperature and stirred for another 2.5 hours. The resulting solution was mixed with 10 mL of dichloromethane, 1M citric acid was added dropwise to adjust the pH to 4˜5, the organic phase was dried with anhydrous magnesium sulphate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (S)-1-(methylsulfonyl)pyrrolidin-3-yl methanesulfonate 11c (153 mg) as a yellow solid, which was directly used in the next step without further purification.
Reaction SMILES: [C:1]1([N:7]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35].C(O)C.C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:35].[C:1]1([N:7]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:43])[NH2:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2sc(CNc3ccc(C#N)cc3)nc2c1)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Yield: 82 %

Procedure:
Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 82% of theory, C26H25N5O3S (487.58) Rf value: 0.21 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid) EKA mass spectrum: (M+H)+ =488
Reaction SMILES: C(ON[C:10]([C@H:12]1[C@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:11])C1C=CC=CC=1.C[OH:33]>[Pd]>[OH:18][C@@H:17]1[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C@H:12]1[C:10]([OH:33])=[O:11]
Reactant: CO
Reactant: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Agent: [Pd]
Product: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@@H](O)[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The above compound (6) (316 mg) was dissolved in methanol (25 mL) and 10% Pd—C (40 mg) was added, and then the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the titled compound (242 mg) as a colorless powder.
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[NH:13][C:14]1[CH:15]=[C:16]([OH:22])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1.[C:23]([NH:26][C:27]1[CH:28]=[C:29]([S:33]([CH3:36])(=[NH:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)(=[O:25])[CH3:24]>>[OH:22][C:16]1[CH:15]=[C:14]([NH:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:35]=[S:33]([C:29]4[CH:28]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[CH:32]=[CH:31][CH:30]=4)([CH3:36])=[O:34])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=1
Reactant: CC(=O)Nc1cccc(S(C)(=N)=O)c1
Reactant: COc1cc(O)cc(Nc2ccnc3ccc(Br)cc23)c1
Agent: Cl
Product: COc1cc(O)cc(Nc2ccnc3ccc(N=S(C)(=O)c4cccc(NC(C)=O)c4)cc23)c1

Procedure:
The title compound is prepared starting from 3-(6-bromoquinolin-4-ylamino)-5-methoxyphenol (intermediate 5) and S-(3-acetylaminophenyl)-S-methyl-sulphoximine in analogy to the synthesis of the compound of Example 17 (method D).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])([O-])=O.[Na+].[Na+].[CH3:10][S:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>O.CO>[OH:3][NH:2][C:16](=[NH:17])[C:15]1[CH:18]=[CH:19][C:12]([S:11][CH3:10])=[CH:13][CH:14]=1
Reactant: NO
Reactant: CSc1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSc1ccc(C(=N)NO)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
Hydroxylamine hydrochloride (104 mg, 1.5 mmol) and Na2CO3 (80 mg, 0.75 mmol) were dissolved in 0.5 mL of water. A solution of 4-methylsulfanyl-benzonitrile (223 mg, 1.5 mmol) in 4 mL of methanol was added and the combined solution was stirred at RT for about 48 h. After removal of the solvent, the precipitate was washed with water, filtered and dried to give N-hydroxy-4-methylsulfanyl-benzamidine (203 mg, 75%) which was used without further purification.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3](O)=[O:4].[NH2:28][CH2:29][CH2:30][OH:31].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH3:24])=[CH:20][CH:21]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3]([NH:28][CH2:29][CH2:30][OH:31])=[O:4]
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)O)ccc2-3)cc1
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)NCCO)ccc2-3)cc1
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 2-hydroxy-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (Example 127, 18 mg, 0.050 mmol) in DMF (1 mL) was added 2-aminoethanol (5.45 mg, 0.089 mmol), 4-methylmorpholine (0.033 mL, 0.29 mmol) and BOP (39.4 mg, 0.089 mmol). The reaction mixture was stirred overnight and was then purified by preparative HPLC (Phenomenex Luna 5 u C18 21.2×100 mm, Solvent A: 90% water with 10% MeOH and 0.1% TFA, Solvent B: 90% MeOH with 10% water and 0.1% TFA, Gradient: 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.9 min) to give 2-hydroxy-N-(2-hydroxyethyl)-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetamide (14.5 mg, 0.033 mmol, 67.4% yield): product HPLC ret. time=8.79 min. (condition G); LC/MS M+1=407.1; 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (1H, d, J=7.92 Hz), 7.72 (2H, d, J=8.36 Hz), 7.44-7.55 (2H, m), 7.37 (2H, d, J=8.36 Hz), 5.07 (1H, s), 3.58-3.69 (2H, m), 3.34-3.43 (2H, m), 3.05 (4H, s), 2.59-2.74 (2H, m), 1.61-1.80 (2H, m), 0.97 (3H, t, J=7.37 Hz).
Reaction SMILES: [CH:1]([C:4]1[C:12]([O:13]C2CCCCO2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2C1CCCCO1)([CH3:3])[CH3:2].C(C1C(O)=CC=C2C=1C=NN2C1CCCCO1)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[CH:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([CH3:3])[CH3:2]
Reactant: CC(C)c1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Agent: CC(C)c1c(O)ccc2c1cnn2C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)c1c(O)ccc2[nH]ncc12
Temperature: 25 °C
Yield: 280.2 %

Procedure:
A mixture of 4-isopropyl-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (301 mg, 0.871 mmol) and 4-isopropyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol (586 mg, 2.25 mmol) was made into a solution of the mixture in dichloromethane (26 ml), followed by adding thereto trifluoroacetic acid (6.5 ml), and the resulting mixture was stirred for 4 hours while being maintained at room temperature. The reaction solution was diluted with ethyl acetate, neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate, and the extract solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain 4-isopropyl-1H-indazol-5-ol (430 mg, 78%).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=1)(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1(=O)[O:35][C:33](=[O:34])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.Cl.C1C[O:45][CH2:44]C1>>[C:16]([O:15][C:13]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([C:1](=[O:3])[CH:2]=[C:44]([C:32]2([C:33]([OH:35])=[O:34])[CH:31]=[CH:39][CH:38]=[CH:37][CH2:36]2)[OH:45])=[CH:5]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C1CCOC1
Reactant: CC(=O)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Product: CC(C)(C)OC(=O)n1cc(C(=O)C=C(O)C2(C(=O)O)C=CC=CC2)c2ccccc21
Temperature: 25 °C
Yield: 30 %

Procedure:
To a solution of 777 mg (3 mmol) of 3-acetyl-1-tert-butoxycarbonyl-indole in THF (10 ml) was added 3.6 ml (3.6 mmol) of 1M LHMDS in THF at −78° C. The mixture was gradually warmed to room temperature. The mixture was cooled again to −78° C. and treated with 525 mg (3.6 mmol) of phthalic anhydride. The reaction solution was warmed to room temperature and mixed with ice water. The solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried, and then concentrated. The obtained residue was crystallized from ethyl acetate-n-hexane to give 362 mg of the titled compound. Yield: 30%.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)=[CH:3][CH:2]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:20]=[CH:19][C:17]([NH:18][CH2:27][C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=3)=[CH:16][CH:15]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(-c2cccc3c2oc2ccccc23)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(CNc2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Yield: 78 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-dibenzo[b,d]furan-4-ylaniline and 4-(trifluoromethyl)benzaldehyde gave the title compound as a colorless oil (78%). 1H NMR (DMSO-d6, 300 MHz) δ 8.15 (d, 1H, J=7.1 Hz), 8.01 (m, 1H), 7.7548 (m, 9H), 7.44-7.37 (m, 2H), 6.74 (m, 3H), 4.47 (m, 2H). M−(LC/MS(ESI)): 416.2; M+(LC/MS(ESI)): 418.2. HPLC (Condition A), Rt: 5.72 min (HPLC purity: 99.3%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]([F:26])([F:25])[S:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=O)(=[O:15])=[O:14].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:19]([C:18]3[CH:22]=[CH:23][CH:24]=[C:16]([S:13]([C:12]([F:26])([F:11])[F:25])(=[O:14])=[O:15])[CH:17]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: N=C(NO)c1cccnc1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)C(F)(F)F)c1
Agent: N
Product: O=S(=O)(c1cccc(-c2nc(-c3cccnc3)no2)c1)C(F)(F)F

Procedure:
The title compound was prepared according to the procedure of Example 1 using N-hydroxynicotinimidamide (Aldrich) and the compound of Example 6B. 1H NMR (300 MHz, DMSO-d6) δ 7.73 (dd, J=4, 5.0 Hz, 1 H), 7.85 (t, J=8 Hz, 1 H), 8.13 (m, 1 H), 8.43 (m, 1 H) 8.5 (m, 1 H), 8.6 (m, 1 H), 8.92 (m, 1 H), 9.37 (m, 1 H) ppm; MS (DCI/NH3) m/z 356 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([NH:13][CH3:14])=[O:12].[N+](C1C=C(S(O[CH2:28][C@@H:29]2[CH2:31][O:30]2)(=O)=O)C=CC=1)([O-])=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:10][C:11]([NH:13][CH3:14])=[O:12])=[C:2]([O:1][CH2:28][C@@H:29]2[CH2:31][O:30]2)[CH:7]=1
Reactant: CNC(=O)Cc1ccc(OC)cc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)Cc1ccc(OC)cc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A mixture of 2-(2-hydroxy-4-methoxyphenyl)-N-methylacetamide (15 mg, 0.076 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (20 mg, 0.076 mmol) and Cs2CO3 (30 mg, 0.091 mmol) in DMF (1.5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-100% ethyl acetate in petroleum spirit) to give the subtitled compound (18 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[CH:19][CH:18]=1.C1C(=O)N([Cl:40])C(=O)C1>>[Cl:40][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@H:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Cl
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)cc1
Yield: 8.3 %

Procedure:
Following General Procedure H, (R)-tert-butyl 1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethylcarbamate (300 mg, 0.67 mmol) was reacted with NCS (110 mg, 0.87 mmol) to afford the desired product (27 mg, 11%) as a yellow solid: ESI MS m/z 485 [C25H25ClN2O4S+H]+.
Reaction SMILES: [I:1][CH3:2].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([CH:14]([OH:23])[C:15]2[N:22]3[C:18]([S:19][CH:20]=[CH:21]3)=[CH:17][N:16]=2)[CH2:12][C@H:11]([S:24][C:25]2[C@H:26]([CH3:42])[C@@H:27]3[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:28]3[C:29]=2[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]>>[I-:1].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([CH:14]([OH:23])[C:15]2[N:16]([CH3:2])[CH:17]=[C:18]3[N+:22]=2[CH:21]=[CH:20][S:19]3)[CH2:12][C@H:11]([S:24][C:25]2[C@H:26]([CH3:42])[C@@H:27]3[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:28]3[C:29]=2[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]
Reactant: CI
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3ncc4sccn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3n(C)cc4scc[n+]34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 83.4 %

Procedure:
Iodomethane (0.76 g) is added to 62.8 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-5-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (stereoisomer A) described in Example 12-d), and the mixture is stirred in an argon atmosphere in a light-shielded state at room temperature for 19.5 hr. The excess reagent is removed by evaporation under reduced pressure, and the residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 65 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(6-methylimidazo[5,1-b]thiazolium-5-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide (sterecisomer A) as a milky white, glass-like solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)[C:3]=1[C:23]([OH:25])=O.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([CH3:38])=[C:36]([C:39](O)=[O:40])[C:35]([C:42]3[CH:43]=[N:44][CH:45]=[N:46][CH:47]=3)=[N:34]2)=[CH:29][C:28]=1[C:48]([F:51])([F:50])[F:49].[N:52]1([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:56][CH2:55][CH2:54][CH2:53]1>>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([CH3:38])=[C:36]([C:39]([N:60]3[CH2:61][CH2:62][CH:57]([N:52]4[CH2:56][CH2:55][CH2:54][CH2:53]4)[CH2:58][CH2:59]3)=[O:40])[C:35]([C:42]3[CH:43]=[N:44][CH:45]=[N:46][CH:47]=3)=[N:34]2)=[CH:29][C:28]=1[C:48]([F:50])([F:49])[F:51].[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[N:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)[C:3]=1[C:23]([N:60]1[CH2:61][CH2:62][CH:57]([N:52]2[CH2:56][CH2:55][CH2:54][CH2:53]2)[CH2:58][CH2:59]1)=[O:25]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1c(C(=O)O)c(-c2cncnc2)nn1-c1cccc(C(F)(F)F)c1
Reactant: Cc1c(C(=O)O)c(-c2cncnc2)nn1-c1ccc(Br)c(C(F)(F)F)c1
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)c(-c2cncnc2)nn1-c1ccc(Br)c(C(F)(F)F)c1
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)c(-c2cncnc2)nn1-c1cccc(C(F)(F)F)c1
Yield: 20 %

Procedure:
In analogy to the procedure described in Example 160E], a mixture of 5-methyl-3-pyrimidin-5-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 1-(4-bromo-3-trifluoromethyl-phenyl)-5-methyl-3-pyrimidin-5-yl-1H-pyrazole-4-carboxylic acid and 4-(1-pyrrolidinyl)piperidine gave a mixture of the title compounds. Purification by reversed phase HPLC (MeCN:H2O) afforded [1-(4-bromo-3-trifluoromethyl-phenyl)-5-methyl-3-pyrimidin-5-yl-1H-pyrazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (Example 174) and [5-methyl-3-pyrimidin-5-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone as a white solid (20%). MS: 485.4 (MH+).
Reaction SMILES: ClC1C=[CH:38][C:37](F)=[CH:36][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=1)=[O:5].[CH3:41][N:42]1C(C(Cl)=O)=CC(C)=[N:43]1>>[F:35][C:31]1[CH:30]=[C:29]([NH:28][C:24]2[N:23]=[C:22]([C:21]3[C:13]([C:9]4[CH:8]=[C:7]([NH:6][C:4]([C:3]5[N:42]([CH3:41])[N:43]=[C:37]([CH3:38])[CH:36]=5)=[O:5])[CH:12]=[CH:11][CH:10]=4)=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=34)[CH:27]=[CH:26][N:25]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)c1cc(F)ccc1Cl
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Product: Cc1cc(C(=O)Nc2cccc(-c3nn4ccccc4c3-c3ccnc(Nc4cccc(F)c4)n3)c2)n(C)n1

Procedure:
In an analogous procedure to Example 11, 40 mg of the title compound was prepared from 79 mg of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride to give the product as a white solid: 1H NMR (d6-DMSO, 300 MHz) δ 2.23 (s, 3H), 4.02 (s, 3H), 6.62 (d, 1H, J=5.2 Hz), 6.77 (td, 1H, J=9.0 and 2.3 Hz), 6.87 (s, 1H), 7.18 (td, 1H, J=6.9 and 1.3 Hz), 7.29-7.38 (m, 2H), 7.48-7.57 (m, 3H), 7.84 (d, 1H, J=10.8 Hz), 7.93 (d, 1H, J=6.4 Hz), 8.11 (s, 1H), 8.36 (d, 1H, J=5.2 Hz), 8.55 (d, 1H, J=8.8 Hz), 8.90 (d, 1H, J=6.8 Hz), 9.85 (s, 1H), and 10.28 (s, 1H); HRMS calcd for C29H23FN8O: 518.1979, found: 519.2060 (M+H+).