Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[CH:26]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Fc1ccccc1-c1cc(CCl)ccn1
Product: COc1ccc(N(Cc2ccnc(-c3ccccc3F)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(2-fluorophenyl)pyridine (222 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[N:7]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[OH:11][C:9]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(O)n(-c2cccc(OC)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(-n2nc(C(=O)O)cc2O)c1

Procedure:
To a solution of 300 mg of 5-Hydroxy-1-(3-methoxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester in 5 ml of THF, 1 ml of a 1 M aqueous NaOH solution was added. After 3 h the reaction was acidified to pH 1 with diluted aqueous hydrochloric acid and the organic solvent was removed under reduced pressure. The precipitated product was collected by filtration and was used in the subsequent reaction. Yield: 267 mg.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:15]([N:22]([C@@H:30]([CH3:33])[CH:31]=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:23]([N:22]([C@H:30]([C@H:31]([OH:32])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4])[CH3:33])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCCCCCCCCBr
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Agent: II
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Yield: 44.7 %

Procedure:
To a suspension of Mg (155 mg, 6.38 mmol) and a few crystals of I2 in THF (3.1 mL), an aliquot of 1-bromoundecane (0.25 mL, 1.12 mmol) was added and the mixture was stirred at 60° C. until the red color of the solution disappeared. Then the remainder of 1-bromoundecane (0.46 mL, 2.07 mmol) was added and the reaction was stirred at room temperature for 1 h. The Grignard solution formed thereof was cooled down to 0° C. and a solution of aldehyde 4 (323.5 mg, 1.28 mmol) in THF (1.6 mL) was added via cannula. After stirring overnight at room temperature, the reaction was quenched with HCl (3N, 10 mL) extracted with EtOAc (3×10 mL), washed successively with NaHCO3 (20 mL, sat. aq.) and brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography on silica (100% hexane to 10:1 hexane/EtOAc) to obtain a mixture of diastereoisomers. Further purification by HPLC on silica (95:5 to 80:20 hexane/MTBE) afforded pure anti alcohol 29 as a colorless oil (205 mg, 39% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].N>CO.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH2:7][NH2:8])[CH:9]=1
Reactant: N#Cc1cc(F)ccc1-n1cncn1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc(F)ccc1-n1cncn1
Yield: 78 %

Procedure:
A suspension of 5-fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile (200 mg, 1.0 mmol) in methanol saturated with ammonia (30 mL) was stirred in the presence of Raney nickel (50% slurry in water, washed with methanol, catalytic amount) under a hydrogen atmosphere (balloon) for 2 days. The reaction mixture was filtered through Celite and concentrated to give the title compound as a light green foam (150 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.69 (br, 2H) 7.8 (br s, 1H), 7.42 (s, 1H), 7.29 (s, 1H), 7.17 (s, 1H). 3.98 (br s, 2H)
Reaction SMILES: O[CH:2]([C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].C(N(S(F)(F)[F:19])CC)C.O.[OH-].[Na+]>C(Cl)Cl>[F:19][CH:2]([C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)c1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(F)c1nc2ccccc2[nH]1
Temperature: -78 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
A solution of 3.24 g (0.02 mole) of 1-hydroxyethylbenzimidazole in 50 ml of methylene chloride was added to a solution of 2.44 ml (0.02 mole) of diethylaminosulfur trifluoride in 50 ml of methylene chloride cooled to -78° C. and under a nitrogen atmosphere. The reaction mixture was allowed to warm slowly to room temperature where it was stirred for 4 hours. The mixture was poured into water, the pH adjusted to 8 with aqueous sodium hydroxide solution and the organic layer separated and dried. Removal of the solvent gave 1.25 g of a brown oil which was chromatographed on 100 g of silica gel using 5% methanol chloroform as the eluent, 845 mg.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[N:20]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:10]([OH:28])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.[F:55][C:56]([F:70])([F:69])[C:57]1[CH:58]=[C:59]([CH:62]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:64]=1)[CH2:60]Br>>[CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[N:20]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:10]([O:28][CH2:60][C:59]1[CH:62]=[C:63]([C:65]([F:67])([F:68])[F:66])[CH:64]=[C:57]([C:56]([F:55])([F:69])[F:70])[CH:58]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCn1nnnc1[C@]1(F)C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: COCCOCn1nnnc1[C@]1(F)C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
(1R*,2R*,5S*,6S*)-8-benzyl-6-fluoro-6-[1-(2-methoxyethoxymethyl)-1H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 45; 205 mg, 0.44 mmol) was added to a stirred mixture of sodium hydride (60% in oil, 60 mg, 1.5 mmol, washed twice with iso-hexane) in THF (2 ml) followed by 18-crown-6 (40 mg, 1.5 mmol) and 3,5-bis(trifluoromethyl)benzyl bromide (0.4 ml, 2.16 mmol) at room temperature. The reaction mixture was warm up to reflux and stirred at room temperature overnight, then quenched with saturated aqueous NH4Cl and extracted into diethyl ether. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 10-70%) to give the title compound (303 mg, 97%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[C:4]([CH3:17])[CH:3]=1.[I-:18].[Na+].CNCCNC>O1CCOCC1.[Cu]I>[I:18][C:2]1[S:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[C:4]([CH3:17])[CH:3]=1
Reactant: CCCc1ccc(Cc2sc(Br)cc2C)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCc1ccc(Cc2sc(I)cc2C)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a mixture of 5-bromo-3-methyl-2-(4-propylbenzyl)thiophene (46, 0.86 g, 2.77 mmol), sodium iodide (0.83 g, 5.53 mmol) and copper(I) iodide (0.053 g, 0.277 mmol) in dioxane (5.2 mL) was added N,N′-dimethylethylenediamine (0.060 mL, 0.553 mmol). The resulting mixture was heated to 110° C. and stirred for 16 hours. After cooling to room temperature, the reaction mixture was filtered through a plug of Celite® and then washed with EtOAc (50 mL). The filtrate was washed with brine and dried over MgSO4. The organic phase was evaporated under vacuum to provide 5-iodo-3-methyl-2-(4-propylbenzyl)thiophene 47 (0.95 g, 2.66 mmol, 96%) as a yellow oil, which was used without further purification.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]([CH2:28][C:29](Cl)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:29](=[O:30])[CH2:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CC(C)(C)CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(OC(=O)CC(C)(C)C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with tert-butylacetyl chloride (9.0 μl) and N,N-diisopropylethylamine (28 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[C:5](=O)[NH:4][C:3]=1[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18].P(Cl)(Cl)([Cl:26])=O>CCCCCCC.C(OCC)(=O)C>[Cl:26][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[N:4]=1
Reactant: CCCCOC(=O)c1[nH]c(=O)c2ccc(OC(C)C)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(Cl)c2ccc(OC(C)C)cc2c1O

Procedure:
2.0 g of compound B from Example 1e) were reacted with phosphorus oxychloride analogously to 1f). After chromatography using heptane/ethyl acetate (4:1) on silica gel, 1.5 g of product were isolated; m.p. 116-118° C. (from petroleum ether).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15](=[O:29])[C@@H:16]1[CH2:20][C@@H:19]([OH:21])[CH2:18][N:17]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[F:30][C:31]1[CH:32]=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[C:35](O)[CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:30][C:31]1[CH:36]=[CH:35][C:34]([N+:38]([O-:40])=[O:39])=[C:33]([CH:32]=1)[O:21][C@@H:19]1[CH2:18][N:17]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C@H:16]([C:15]([O:14][CH3:13])=[O:29])[CH2:20]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CN1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
Diethylazodicarboxylate (1.76 ml) was added dropwise to a solution of N-Boc-trans-4-hydroxy-L-proline methyl ester (2.74 g), 5-fluoro-2-nitrophenol (1.47 g) and triphenylphosphine (2.93 g) in dichlormethane under cooling at 0° C. The coolant was removed after 20 min and the reaction mixture was stirred at room temperature over the weekend. The solvent was evaporated and the residue war purified by chromatography to give the desired product.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([OH:24])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12])[CH3:6].Cl[C:27]1[N:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[F:25][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:23]=[C:22]([CH:21]=[C:10]([C:11](=[O:12])[NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)[CH:9]=1)[O:24][C:27]1[N:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=1)[CH3:6]
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)COC(F)F)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N(C)C)cn3)cc(O[C@@H](C)COC(F)F)c2)cn1
Temperature: 140 °C
Reaction time: 5 h
Yield: 55.3 %

Procedure:
A mixture of 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (0.19 g, 0.54 mmol), 5-chloro-N,N-dimethyl-pyrazine-2-carboxamide (100 mg, 0.54 mmol) and potassium carbonate (149 mg, 1.08 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 5 hours and the mixture reduced in vacuo. Ethyl acetate (50 mL) was added and the mixture washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo. The crude residue was chromatographed on silica, eluting with 0-5% methanol in DCM, to give the desired compound (150 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C1COCCN1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nccc(N2CCOCC2)n1
Yield: 90.5 %

Procedure:
To a cooled (0° C.) suspension of 2,4-dichloropyrimidine (20)(1.0 g, 6.7 mmol) in ethanol (20 ml), which was stirred under an inert atmosphere, was added triethylamine (1.4 ml, 10.1 mmol) and then morpholine (0.59 ml, 6.7 mmol). The mixture was maintained at this temperature for 3 hours whereupon it was concentrated in vacuo, diluted with NaOH (20 ml, 1M) and extracted with EtOAc (3×20 ml). The organic extracts were combined, dried (Na2SO4), filtered and concentrated in vacuo to give a colorless solid. The crude residue was re-crystallised using EtOAc/Hexanes to give the title compound (1.21 g, 90%) as a colourless solid which required no further purification. m/z (LC-MS, ESP): 200 [M+H]+, R/T=3.26 mins
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH2:64])[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1.[CH3:65][C:66]1[C:78]([CH3:79])=[CH:77][C:69]2[N:70]([CH2:73][C:74](O)=[O:75])[CH:71]=[N:72][C:68]=2[CH:67]=1>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH:64][C:74](=[O:75])[CH2:73][N:70]2[C:69]3[CH:77]=[C:78]([CH3:79])[C:66]([CH3:65])=[CH:67][C:68]=3[N:72]=[CH:71]2)[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1
Reactant: Cc1cc2ncn(CC(=O)O)c2cc1C
Reactant: NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Product: Cc1cc2ncn(CC(=O)NC(Cc3cc(F)cc(F)c3)c3ncoc3-c3ccc(Cl)cc3)c2cc1C

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 33G and 2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid. 1H NMR (400 MHz, dmso) δ 9.36 (d, J=8.3 Hz, 1H), 9.11 (s, 1H), 8.55 (s, 1H), 7.63-7.53 (m, 3H), 7.45 (d, J=8.3 Hz, 2H), 7.20 (s, 1H), 6.98 (d, J=8.7 Hz, 1H), 6.88 (d, J=7.2 Hz, 2H), 5.36 (d, J=7.5 Hz, 1H), 5.17-5.01 (m, 2H), 3.27-3.10 (m, 2H), 2.35 (s, 3H), 2.29 (s, 3H). MS (m/z) 521.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH3:14][C:15]1[CH:31]=[CH:30][C:18]2[S:19][C:20]([CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)O)=[CH:21][C:17]=2[CH:16]=1>>[OH:6][C:5]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:7])[C:4]=1[CH:22]([C:20]1[S:19][C:18]2[CH:30]=[CH:31][C:15]([CH3:14])=[CH:16][C:17]=2[CH:21]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc2sc(C(O)c3ccccc3)cc2c1
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Product: Cc1ccc2sc(C(C3=C(O)C(C)(c4ccccc4)C3=O)c3ccccc3)cc2c1

Procedure:
Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with (5-methyl-benzo[b]thiophen-2-yl)-phenyl-methanol to give the title compound as a colorless solid. MS: 409.3 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2C(=O)C3=CC=CC=C3C2=O)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN.[NH4+].[OH-]>C(O)C>[NH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
A mixture of 2.62 g (6.35 mmole) of N-[[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl]phthalimide, 1.21 ml (1.25 g, 25 mmole) of 100% hydrazine hydrate, and 35 ml of absolute ethanol was stirred at room temperature for 7.5 hours. During this time all of the solid gradually dissolved, followed by precipitation. Glacial acetic acid (3.7 ml) was added, and stirring was continued overnight. The white solid was then removed by filtration, and the filtrate was concentrated at room temperature. The residual oil was taken up in 100 ml of ether and washed with 2×50 ml of saturated aqueous Na2CO3 solution. Next, the product was extracted by shaking the ethereal solution with 50 ml of 0.5N HCl. The aqueous layer was separated and basified by addition of excess saturated Na2CO3. The product, which oiled out, was extracted with 100 ml of ether. The other phase was dried (Na2SO4), filtered, and concentrated at 30° C. to give 1.58 g (88%)of a very pale yellow, viscous oil, homogeneous by TLC in 95:5:0.5 CH2Cl2 -MeOH-concd. NH4OH.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:7](=[O:16])[C@H:6]1[NH2:17])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[C:1]([O:4][C@@H:5]1[N:8]([Si:9]([C:12]([CH3:13])([CH3:15])[CH3:14])([CH3:10])[CH3:11])[C:7](=[O:16])[C@H:6]1[NH:17][C:32](=[O:33])[CH2:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)O[C@H]1[C@H](N)C(=O)N1[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C
Yield: 90.6 %

Procedure:
To a solution of 0.387 g of (3S,4S)-4-acetoxy-3-amino-1-t-butyldimethylsilyl-2-oxoazetidine in 20 ml of THF is added 0.24 g of triethylamine under ice-cooling, and then, a solution of 0.32 g of phenylacetyl chloride in THF is added dropwise. The mixture is stirred under ice-cooling for one hour, the insolubles are filtered off, and the filtrate is concentrated under reduced pressure. Purifying the residue on a silica gel column (ethyl acetate:n-hexane-1:2) yields 0.511 g of (3S,4S)-4-acetoxy-1-t-butyldimethylsilyl-3-phenylacetamido-2-oxoazetidine.
Reaction SMILES: C(OC([N:11]([CH2:28][C:29]([N:31]1[CH2:35][C@@H:34]([F:36])[CH2:33][C@H:32]1[C:37]#[N:38])=[O:30])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>CN(C)C=O.[C].[Pd]>[N:22]1([C:20]([C:15]23[CH2:14][CH2:13][C:12]([NH:11][CH2:28][C:29]([N:31]4[CH2:35][C@@H:34]([F:36])[CH2:33][C@H:32]4[C:37]#[N:38])=[O:30])([CH2:19][CH2:18]2)[CH2:17][CH2:16]3)=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCCCC3)(CC1)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)N3CCCCC3)(CC1)CC2
Reaction time: 0.67 h
Yield: 88.7 %

Procedure:
(2S,4S)-1-[[N-Benzyloxycarbonyl-N-[4-(piperidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (20.0 mg) and 10% palladium carbon (12.0 mg) were dissolved in dimethylformamide (0.5 mL). While the solution was chilled in an ice bath, ammonium formate (43.1 mg) was added and the mixture was stirred for 40 minutes at the same temperature. Subsequently, the reaction mixture was filtered through a Celite pad and diluted with ethyl acetate. The organic layer washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluant:dichloromethane:methanol=10:1) to give (2S,4S)-1-[[N-[4-(piperidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (13.2 mg).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH2:6]([O:13][C:14]1[C:15]([CH2:25][CH:26]([CH3:28])[CH3:27])=[N+:16]([O-:24])[C:17]([O:22][CH3:23])=[C:18]([CH2:20][OH:21])[N:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.ClCCl.C(N(CC)CC)C>C(OCC)C>[CH2:6]([O:13][C:14]1[C:15]([CH2:25][CH:26]([CH3:28])[CH3:27])=[N+:16]([O-:24])[C:17]([O:22][CH3:23])=[C:18]([CH2:20][O:21][S:1]([CH3:4])(=[O:3])=[O:2])[N:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1c(CO)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1c(COS(C)(=O)=O)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Reaction time: 0.5 h

Procedure:
At 0° C., 52 μl of mesyl chloride was added to a mixture of 210 mg of 3-benzyloxy-5-hydroxymethyl-6-methoxy-2-isobutylpyrazine 1-oxide, 2 ml of dichloromethane and 184 μl of triethylamine. The mixture was stirred for 30 minutes at the same temperature, then diethyl ether was added to the reaction mixture. The mixture was washed with water and dried over magnesium sulfate, then the solvent was removed by evaporation. The residue was purified by a silica gel column chromatography (eluting solvent: 50% by volume of ethyl acetate-n-hexane) to obtain 260 mg of 3-benzyloxy-2-isobutyl-6-methoxy-5-mesyloxymethylpyrazine 1-oxide (Compound B-17) as a colorless oily substance.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([S:9][CH3:10])[C:5]=2[C:11]([C:13]2[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[O:12])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:25].[Na+]>CC(C)=O.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([S:9]([CH3:10])=[O:25])[C:5]=2[C:11]([C:13]2[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)=[O:12])[CH2:3][CH2:2]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1noc(C2CC2)c1C(=O)c1ccc(C(F)(F)F)nc1C
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)c1c(S(C)=O)noc1C1CC1
Reaction time: 5 h
Yield: 51.9 %

Procedure:
1.50 g (0.0043 mol) of (5-cyclopropyl-3-methylsulfanyi-isoxazol-4-yl)-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-methanone are dissolved in 30 ml of acetone/water (2:1 mixture) and 1.02 g (0.0048 mol) of sodium metaperiodate are added in portions at 22° C. After 5 hours, the reaction mixture is concentrated by evaporation using a rotary evaporator. The residue is taken up in water and ethyl acetate. The ethyl acetate phase is dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel (eluant: ethyl acetate/hexane 3/1). 0.8 g (51%) of the desired product is obtained in the form of white crystals (m.p. 96-97° C.).