Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: O=C(Cl)c1ccccc1
Product: O=C(NC1CCCc2c1[nH]c1ccc(Cl)cc21)c1ccccc1

Procedure:
N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and benzoyl chloride in a similar manner as described above to give a pale yellow solid (81% yield). 1H-NMR (CDCl3): δ 9.02 (s, 1H), 7.79-7.73 (m, 2H), 7.54-7.48 (m, 1H), 7.46-7.39 (m, 3H), 7.21 (d, 1H), 7.10 (dd, 1H), 6.45 (d, 1H), 5.32 (m, 1H), 2.72 (m, 2H), 2.30 (m, 1H), 2.01-1.90 (m, 3H); MS m/z 323 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].C[O-:16].[Na+].B(Br)(Br)Br>CO>[Cl:1][C:2]1[C:3]([OH:16])=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: C[O-]
Reactant: O=Cc1cc(C(F)(F)F)cc(Cl)c1F
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: CO
Product: O=Cc1cc(C(F)(F)F)cc(Cl)c1O
Temperature: -78 °C
Reaction time: 21 h

Procedure:
3-Chloro-2-fluoro-5-trifluoromethylbenzaldehyde (5.0 g, 22 mmol) was dissolved in dry CH3OH (50 mL), treated with 25% sodium methoxide solution (30 mL) and heated to reflux for 2 h. After cooling, the volatiles were removed by evaporation and the residue was taken up in H2O (20 mL) plus Et2O (80 mL). The aqueous phase was extracted with Et2O (50 mL), and the combined organic phases were washed with satd NaCl solution (15 mL), dried (Na2SO4) and evaporated. The residue was dissolved in dry CH2Cl2 (50 mL), cooled to −78° C. and treated with BBr3 (1 M solution in CH2Cl2; 25 mL, 25 mmol). After warming to 25° C., the mixture was stirred for 21 h, cooled to −40° C. and quenched by addition of H2O (30 mL). After warming, the aqueous phase was extracted with CH2Cl2 (30 mL), and the combined organic phases were washed with satd NaCl solution (30 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with a 0-20% EtOAc gradient in hexane to give the purified aldehyde (2.7 g): 1H NMR (400 MHz, CDCl3) δ 11.81 (s, 1H), 9.96 (s, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.84-7.77 (m, 1H); EIMS m/z 224.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][O:7][C@H:8]1[O:13][CH2:12][CH2:11][NH:10][C@@H:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CCOC(C)=O>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1)[CH2:6][O:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2OCCN[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: COC(=O)CCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCN1CCO[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Temperature: 60 °C
Yield: 64.4 %

Procedure:
To a solution of 0.259 g (0.64 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine (from example 33) in 2 mL of DMF were added 0.16 g (0.77 mmol) of methyl 6-bromohexanoate, 0.155 g (1.12 nmmol) of K2C03 and 2 crystals of nBu4NI. The resulting solution was heated in a 60° C. bath for 36 h, at which time a tlc indicated incomplete reaction. The bath temperature was raised to 100° C. After 3 h the reaction mixture was cooled and diluted with EtOAc. The EtOAc solution was washed with water (2×), brine and dried over Na2SO4. The filtrate was concentrated and the residue was chromatographed using 30% EtOAc/hexane to isolate 220 mg (65%) of the product. 1H-NMR (400 MHz, CDCl3): δ 1.0-1.4 (m, 4 H), 1.47 (m, J=8 Hz, 2H), 1.95 (m, 1H), 2.2 (t, J=8 Hz, 2H), 2.35 (m, 2H), 2.9 (d, J=13 Hz, 1H), 3.07 (d, J=7 Hz, 1H), 3.62 (s, 3H), 3.81 (td, J=8 Hz and 2 Hz, 1 H), 4.04 (dd, J=10 Hz and 2 Hz, 1H), 4.36 (d, J=7 Hz, 1H), 4.4 (d, J=13 Hz, 1H), 4.79 (d, J=13 Hz, 1H), 7.2-7.4 (m, 7H), 7.66 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]1([C:16]2[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:16]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[CH:18][C:19]([CH2:20][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:22][CH:23]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A mixture of 3-hydroxybenzaldehyde (6.02 g, 49 mmol), 4-phenyl-benzylchloride (10 g, 49 mmol) and potassium carbonate (20 g, 148 mmol) in N,N'-dimethylformamide (100 ml) was stirred at room temperature for 16 h. The mixture was poured into water (500 ml) and stirred for 1 h. The solid formed was filtered off, washed with water (2×200 ml) and heptane (2×75 ml) and dried in vacuo at 50° C. for 16 h affording 12.3 g (87%) of 3-(biphenyl-4-ylmetoxy)benzaldehyde as a solid. TLC showed presence of unchanged 4-phenylbenzylchloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14](Cl)[N:13]=[C:12]([NH2:17])[N:11]=2)[C:7]([CH3:18])=[CH:6][C:5]=1[O:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[C:33]([O:37][C:38](=[O:43])[NH:39][CH2:40][CH2:41][SH:42])([CH3:36])([CH3:35])[CH3:34]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:42][CH2:41][CH2:40][NH:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:43])[N:13]=[C:12]([NH2:17])[N:11]=2)[C:7]([CH3:18])=[CH:6][C:5]=1[O:19][CH3:20]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: COC(=O)c1cc(-c2cc(Cl)nc(N)n2)c(C)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cc(SCCNC(=O)OC(C)(C)C)nc(N)n2)c(C)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.9 %

Procedure:
5-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester (118 mg, 0.38 mmol) obtained in Example 1-2 and potassium carbonate (212 mg, 1.5 mmol) were placed in a reaction vessel, and then N,N-dimethylformamide (1.0 ml) and (2-mercaptoethyl)carbamic acid tert-butyl ester (0.25 ml, 1.5 mmol) were added thereto. The mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate (100 ml), and sequentially washed twice with a saturated aqueous sodium bicarbonate solution (50 ml), twice with water (50 ml), and with a saturated aqueous sodium chloride solution (50 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:2) to yield 5-[2-amino-6-(2-tert-butoxycarbonylaminoethylsulfanyl)pyrimidin-4-yl]-2-methoxy-4-methylbenzoic acid methyl ester (143 mg) as a yellow oily material.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([C:28]([O:30]C)=[O:29])[CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[N:4]1)[CH3:2].[OH-].[Li+]>>[CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[N:4]1)[CH3:2]
Reactant: CCn1ccc(NC(=O)Cc2ccc(Oc3ccnc4cc(OC)c(C(=O)OC)cc34)cc2)n1
Agent: [Li+]
Agent: [OH-]
Product: CCn1ccc(NC(=O)Cc2ccc(Oc3ccnc4cc(OC)c(C(=O)O)cc34)cc2)n1
Yield: 92 %

Procedure:
Using an analogous procedure to that described in Example 8, N-(1-ethylpyrazol-3-yl)-2-[4-(7-methoxy-6-methoxycarbonylquinolin-4-yloxy)phenyl]acetamide was reacted with lithium hydroxide to give the title compound in 92% yield; 1H NMR: (DMSOd6) 1.34 (t, 3H), 3.67 (s, 2H), 3.99 (s, 3H), 4.0-4.06 (m, 2H), 6.43 (d, 1H), 6.55 (d, 1H), 7.29 (d, 2H), 7.49 (d, 2H), 7.53 (s, 1H), 7.58 (d, 1H), 8.58 (s, 1H), 8.71 (d, 1H), 10.71 (s, 1H); Mass Spectrum: M+H+ 447.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]>>[O:29]=[C:25]1[CH2:26][CH2:27][CH2:28][N:24]1[CH2:23][CH2:22][CH2:21][NH:20][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: NCCCN1CCCC1=O
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCCN3CCCC3=O)s2)c(C)[nH]c1=O
Yield: 69 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1-(3-aminopropyl)pyrrolidin-2-one as described in Step 5, Example 24 to give the title compound as a white solid (69% yield). LC/MS: RT 2.42 min; m/e 424.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:6]=1.C(O[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1)(C)C.C([Li])CCC.CCCCCC>C1COCC1>[CH3:35][C:30]1([CH3:36])[C:31]([CH3:34])([CH3:33])[O:32][B:28]([C:2]2[CH:3]=[C:4]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:6]=2)[O:29]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)n1cc(I)cc1C(=O)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1

Procedure:
At −78° C. to a solution of 2-benzyl 1-tert-butyl 4-iodo-1H-pyrrole-1,2-dicarboxylate (10.0 g, 23.4 mmol), and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.6 mL, 47 mmol) in THF (120 mL) was added dropwise a solution of 2.5 M n-butyllithium in hexane (11.2 mL, 28.1 mmol) with stirring. After completion of addition the mixture was stirred at this temperature for 35 min and then 2.5 M n-butyllithium in hexane (1.87 mL, 4.68 mmol) was added and stirred for another 30 minutes. The reaction was quenched with sat. NH4Cl solution and then diluted with EtOAc. The organic layer was separated, washed with water twice, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The product was isolated by chromatography eluting with 0 to 10% EtOAc in hexanes. LCMS calculated for C19H23BNO6 (M−[tBu+1]+1)+: m/z=372.2. found: 372.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C([O-])([O-])=O.[Cs+].[Cs+].C(O)(C)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[C:18]([O:19][CH3:20])[CH:17]=2)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(-c2cc(Cl)nc(SC)n2)cc1OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
Argon is bubbled through a mixture of 4,6-dichloro-2-(methylthio)pyrimidine [4.98 g, 25.55 mmol, Intermediate (29)], 3,4-dimethoxyphenylboronic acid [3.874 g, 21.29 mmol, Intermediate (32)], and Cs2CO3 (17.34 g, 53.23 mmol) in ethylene glycol dimethyl ether (56 mL) and water (14 mL), for a period of 15 minutes. To this mixture is added tetrakis(triphenylphosphine)palladium (0) (1.22 g, 1.06 mmol) the reaction vessel is heated to 100° C. After stirring overnight the mixture is diluted with water (250 mL) and extracted three times with EtOAc (100 mL). The organic extracts are combined, washed with brine (100 mL), and dried over magnesium sulfate. The mixture is filtered and concentrated to provide a solid that is dissolved in boiling isopropyl alcohol (40 mL) and allowed to cool to ambient temperature. After standing for 24 hours the solid is collected by filtration, washed with cold isopropyl alcohol and dried under high vacuum to afford 4-chloro-6-(3,4-dimethoxy-phenyl)-2-methylsulfanyl-pyrimidine [5.28 g, 83.5%, Intermediate (48)].
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=3)[C:19](=[O:27])[CH2:20][CH2:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)[C:19](=[O:27])[CH2:20][CH2:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(C(=O)OC)cc3)C(=O)CCC3CCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(C(=O)O)cc3)C(=O)CCC3CCCC3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl 4-{[{4-[(4-butylphenyl)ethynyl]benzyl}(3-cyclopentylpropanoyl)amino]methyl}benzoate and NaOH 1M as a yellow foam (77%). 1H NMR (CDCl3, 300 MHz) δ 8.15-8.02 (m, 2H), 7.56-7.40 (m, 4H), 7.33-7.22 (m, 2H), 7.21-7.08 (m, 4H), 4.69-4.58 (m, 2H), 4.54-4.43 (m, 2H), 2.61 (t, J=7.7 Hz, 2H), 2.49-2.35 (m, 2), 1.81-1.0 (m, 15H), 0.93 (t, J=7.3 Hz, 3H). M− (ESI): 520.4; M1(ESI): 522.3. HPLC, Rt: 5.71 min (Purity: 99.2%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+]>>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C:13]([CH2:14][CH:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)=[O:28])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@H]3C(CC(=O)[C@]12C)[C@@]1(C)CC[C@@H](O)C[C@H]1C[C@H]3O
Temperature: 30 °C
Reaction time: 24 h

Procedure:
Bacillus sp. TTUR 2-M4-336 was cultivated under shaking at the temperature of 30° C. for 24 hours in a test tube containing 20 ml of the culture medium of above composition except cholic acid and sodium hydroxide were excluded, thus a bacterium solution was prepared. 20 ml of above culture medium was placed into a test tube(30φ×190 mm), 40 ml of said bacterium solution was aseptically inoculated therein, and the bacterium in the test tube was cultivated under agitation (300 rpm) at the aeration rate 21/min. at 30° C. for three days. A trace amount of antifoaming agent (EINOL; trade name; BIOTT Co. LTD) was added during this operation. And thereafter, the same procedure as Example 23 was proceeded and 12-keto-cholic acid was obtained. The ratio in the product was cholic acid 0.7%, 12-keto-cholic acid 99.3% (recovery rate: 99.2% ).
Reaction SMILES: [CH:1]#[CH:2].[C:3]1(=[O:10])[NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>>[CH:1]([N:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:10])=[CH2:2]
Reactant: C#C
Reactant: O=C1CCCCCN1
Product: C=CN1CCCCCC1=O
Yield: 77.9 %

Procedure:
Example 1 was carried out without addition of a cocatalyst. The amount of ethyne taken up was 0.69 mol per mole of ε-caprolactam. The distillative workup yielded N-vinyl-ε-caprolactam in a yield of 77.9%. A viscid distillation residue was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][C@@H:22]([NH:67]C(OC(C)(C)C)=O)[C:23]([O:25][C@H:26]1[C@@H:30]([OH:31])[C@H:29]([N:32]2[CH:40]=[N:39][C:38]3[C:33]2=[N:34][CH:35]=[N:36][C:37]=3[NH2:41])[O:28][C@H:27]1[CH2:42][O:43][P:44]([O:47][C@H:48]1[CH2:52][C@H:51]([N:53]2[CH:58]=[CH:57][C:56]([NH2:59])=[N:55][C:54]2=[O:60])[O:50][C@@H:49]1[CH2:61][O:62][P:63]([OH:66])([OH:65])=[O:64])([OH:46])=[O:45])=[O:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[NH2:67][C@H:22]([CH2:21][CH2:20][CH2:19][NH:18][C:16]([O:15][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:17])[C:23]([O:25][C@H:26]1[C@@H:30]([OH:31])[C@H:29]([N:32]2[CH:40]=[N:39][C:38]3[C:33]2=[N:34][CH:35]=[N:36][C:37]=3[NH2:41])[O:28][C@H:27]1[CH2:42][O:43][P:44]([O:47][C@H:48]1[CH2:52][C@H:51]([N:53]2[CH:58]=[CH:57][C:56]([NH2:59])=[N:55][C:54]2=[O:60])[O:50][C@@H:49]1[CH2:61][O:62][P:63]([OH:66])([OH:65])=[O:64])([OH:46])=[O:45])=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3OC(=O)[C@H](N)CCCNC(=O)OCc3ccccc3)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 91.9 %

Procedure:
Trifluoroacetic acid (0.117 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk67) (30 mg, 0.030 mmol) in dichloromethane (1.1 mL), and the mixture was stirred at room temperature for 35 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-5-(((benzyloxy)carbonyl)amino)pentanoate (Orn(Z)-pdCpA) (Compound tk68) (24.4 mg, 91%).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH:21]([CH:10]2[CH:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:12][NH:8][CH2:9]2)[CH3:22])=[N:25][CH:26]=1
Reactant: CC(Oc1ccc(Cl)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(Oc1ccc(Cl)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reaction time: 4 h
Yield: 54 %

Procedure:
To a solution of 2-{(SR)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine (1.71 g (3.71 mmol) dissolved in CH3CN (50 mL) was added 0.75 mL (5.57 mmol) of 2,2,2-trichloroethyl chloroformate and stirring was continued for 4 hours at RT. Volatiles were removed under vacuo, and the crude was dissolved in AcOH (30 mL) before a total of 1.0 g of Zn dust was added portion wise. After three hours at RT, the reaction mixture was filtered on celite, the solvent removed under vacuo, followed by an extraction with EtOAc/aq. NaHCO3 (basic pH). The organic phases were dried on Na2SO4 and column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 0.74 g (54%) of the title compound as a colorless oil. ES-MS m/e: 373.1 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][O:4][NH:3]1.Br[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][O:4][N:3]1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: O=C1NOCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(OCCN2OCc3ccccc3C2=O)cc1
Yield: 66.6 %

Procedure:
##STR34## The title compound (370 mg, 66%) was prepared from 4-oxo-3,4-dihydro-1H-2,3-benzoxazine (280 mg, 1.87 mmol) (prepared according to the procedure described in Tetrahedron, 22 (1966) 2107) and 4-(2-bromoethoxy)benzaldehyde (430 mg, 1.87 mmol) and K2CO3 (520 mg, 3.74 mmol). mp: 102° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=2[C:25]([F:28])([F:27])[F:26])(=[O:12])=[O:11])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].COC([C@@H]1C[C@@H](S(C2C=CC(F)=CC=2C(F)(F)F)(=O)=O)CN1C(OC(C)(C)C)=O)=O.FC(F)(F)C(O)=O.COC([C@@H]1C[C@@H](S(C2C=CC(F)=CC=2C(F)(F)F)(=O)=O)CN1)=O>ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:22])([F:23])[F:24])=[CH:15][C:14]=2[C:25]([F:27])([F:26])[F:28])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C
Agent: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1
Agent: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2C(F)(F)F)CN1

Procedure:
In analogy to the procedure described in example 253a, (2S,4R)-4-[4-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-benzenesulfonyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester containing (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester was treated with trifluoroacetic acid in dichloromethane to give a mixture of the title compound and (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as yellow oil. MS (ESI): m/z=436.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:27])[CH:12]=[C:13]([NH:15][C:16]([C:18]3[N:19]([CH3:26])[CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=3)=[O:17])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:28]([NH:30][CH2:31][CH2:32][C:33]#[N:34])=[O:29].Cl.[NH2:36][OH:37]>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:27])[CH:12]=[C:13]([NH:15][C:16]([C:18]3[N:19]([CH3:26])[CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=3)=[O:17])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:28]([NH:30][CH2:31][CH2:32][C:33](=[N:36][OH:37])[NH2:34])=[O:29]
Reactant: Cn1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])cn3C)cn2C)cc1C(=O)NCCC#N
Reactant: NO
Agent: Cl
Solvent: CCO
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])cn3C)cn2C)cc1C(=O)NCCC(N)=NO
Reaction time: 24 h

Procedure:
1.2 g of 3-[1-methyl-4-[1-methyl-4-[1-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrile (prepared as reported in J.Med.Chem 22,1296-1301,1979) was suspended in dry ethanol and the solution saturated with dry hydrogen chloride. After 24 hours at room temperature, the solvent was evaporated in vacuum and the residue treated with two equivalents of solution of hydroxylamine in dry ethanol. After 24 hours at room temperature, the solvent was evaporated in vacuum and the residue purified by flash chromatography yielding 500 mg of 3-[1-methyl-4[1-methyl-4[1-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime which was dissolved in a mixture of methanol-dioxane-10% hydrochloric acid (4:1:1) and reduced over Pd catalyst (10% on charcoal) in hydrogen atmosphere (50 psi) in a Parr apparatus. The solution obtained after filtration of the catalyst was evaporated in vacuum, and the solid residue suspended in dry ethanol, and filtered to yield 500 mg of intermediate.