Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[CH:7]2.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc2ccc(=O)[nH]c12
Product: Cc1cccc2ccc(Cl)nc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of 8-methyl-1H-quinolin-2-one (107) (580 mg, 3.6 mmol) and phosphorus oxychloride (5 mL) was stirred at 60° C. overnight. The mixture was then poured onto ice water and extracted with DCM (3×50 mL). The combined extracts were washed with water (2×100 mL) and dried with Na2SO4, and the solvent was removed. The residue was chromatographed on silica gel using 5% to 20% EtOAc in petroleum ether to give product (108) as small colorless crystals (400 mg, 2.3 mmol, 63% yield).
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[NH:8][CH:7]=1)=O.[C:18]1([CH2:30][C:31]([NH2:33])=[O:32])[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[CH:19]=1>>[C:18]1([C:30]2[C:31](=[O:32])[NH:33][C:3](=[O:17])[C:4]=2[C:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=3)[NH:8][CH:7]=2)[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[CH:19]=1
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reactant: COC(=O)C(=O)c1c[nH]c2cc(F)c(F)cc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2cc(F)c(F)cc12

Procedure:
Beginning with (5,6-difluoroindol-3-yl)oxoacetic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([CH2:14][NH:15][CH2:16][C@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=2)[C@H:18]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O.[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O>[CH2:7]([CH2:14][NH:15][CH2:16][C@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:23]=2)[C@H:18]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1ccc2c(c1)CC[C@H](CNCCc1ccccc1)[C@@H]2c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CCNC[C@H]2CCc3cc(OCc4ccccc4)ccc3[C@H]2c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a mixture of cesium carbonate (1.09 g), cis-2-(N-benzylmethylamino)methyl-6-hydroxy-1-phenyl-1,2,3,4-tetrahydronaphthalene (600 mg) and N,N-dimethylformamide (10 cm3) was added benzyl bromide (0.236 cm3). The resulting mixture was warmed to 80° C. and stirred for 2 h. Upon cooling, water (50 cm3) was added and the aqueous mass was extracted with ether (2×50 cm3). The combined ether extracts were washed with water (30 cm3), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure to afford a yellow oil. This was purified by column chromatography [silica, eluting with petroleum ether (b.p. 40-60° C.)-ethyl acetate (15:1)] to afford the title compound (538 mg; 72%) as a light yellow oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:45][CH2:46][CH2:47][C:48]1[CH:57]=[CH:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[N:49]=1>C1COCC1>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH3:29])[C:26]([NH:45][CH2:46][CH2:47][C:48]2[CH:57]=[CH:56][C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[N:49]=2)=[O:27])=[CH:18]1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Reactant: NCCc1ccc2ccccc2n1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1ccc2ccccc2n1
Temperature: -22 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
To a stirred solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (1.59 g, 4.0 mmole) in dry THF (50 mL) at -22° C. was added N-methylmorpholine (0.644 g, 6.3 mmole) and isobutyl chloroformate (0.632 g, 4.6 mmole). The mixture was stirred at -22° C. for 1 hour and then a solution of 2-(2-aminoethyl)quinoline (0.690 g, 4.0 mmole) in dry THF (15 mL) was added. After stirring at this temperature 4 hours the reaction mixture was allowed to stir at room temperature 15 hours. The solvent was removed in vacuo and the residue was taken up in EtOAc and washed with 5% citric acid (2×50 mL), water (2×50 mL), 5% NaHCO3 (3×50 mL), water and brine (2×50 mL). The organic phase was dried over MgSO4 and the solvent evaporated. The residue was flash chromatographed on silica gel, eluting with EtOAc-n-hexane. The oil obtained was triturated with cold Et2O, yielding the product as an amorphous white solid, (0.38 g, 17%); 1H NMR (CDCl3) δ 1.41-1.88 (17H, m), 3.00-3.04 (2H, m), 3.40 (2H, q, J 9.59 Hz), 3.68-3.70 (2H, m), 4.70 (1H, s), 5.43 (1H, br s), 6.90 (1H, d, J 2.23), 6.96-7.22 (4H, m), 7.45-7.55 (2H, m), 7.63-7.70 (2H, m), 7.78 (1H, d, J 8.06), 7.89 (2H, d, J 8.10), 8.03 (1H, d, J 8.46).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([CH2:16][O:17][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:12]([CH3:15])[CH2:13][CH3:14])C1C=CC=CC=1>CO.[Pd]>[Si:18]([O:17][CH2:16][C@@H:11]([NH2:10])[C@@H:12]([CH3:15])[CH2:13][CH3:14])([C:31]([CH3:33])([CH3:34])[CH3:32])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC[C@H](C)[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 82.9 %

Procedure:
A solution of [(1S,2S)-1-(t-butyldiphenylsilyloxymethyl)-2-methylbutyl]carbamic acid benzyl ester (6.72 g, 13.7 mmol) (obtained as described in Reference Example 38(1)) in methanol (200 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (6.72 g) at room temperature for 2 hours. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:methanol (98:2→9:1) as the eluant to afford (1S,2S)-1-(t-butyldiphenylsilyloxymethyl)-2-methylbutylamine (4.04 g, yield 83%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([F:11])[F:10])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([CH:45]=[O:46])=[CH:16][N:17]2[C@@H:22]1[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]1[O:24][C:25](=[O:27])[CH3:26].[Cl-].[NH4+]>O1CCCC1.BrCCBr>[F:10][CH:9]([F:11])[C:6]1[CH:7]=[CH:8][C:3]([CH:45]([C:15]2[C:14]3[C:18](=[CH:19][CH:20]=[CH:21][C:13]=3[F:12])[N:17]([C@@H:22]3[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]3[O:24][C:25](=[O:27])[CH3:26])[CH:16]=2)[OH:46])=[CH:4][CH:5]=1
Reactant: FC(F)c1ccc(Br)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C=O)c3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(O)c3ccc(C(F)F)cc3)c3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
To a mixture of magnesium turnings (71 mg) in tetrahydrofuran (2 ml) was added dropwise a solution of 1-bromo-4-difluoromethylbenzene (587 mg) in tetrahydrofuran (1.5 ml) under being stirred vigorously. The mixture was warmed with a dryer, and thereto was added 1,2-dibromoethane (4 drops). The resultant mixture was vigorously stirred at room temperature till a disappearance of magnesium turnings, and then dropwise added to a solution of the above 4-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole-3-carboxaldehyde (350 mg) in tetrahydrofuran (4 ml) over 10 minutes at −78° C. under argon atmosphere. The mixture was stirred at same temperature for 1 hour, and thereto was added a saturated aqueous ammonium chloride solution (20 ml). The resultant mixture was extracted with ethyl acetate (50 ml) 3 times, and the combined organic layer was dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure to give crude 4-(difluoromethyl)phenyl 4-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indol-3-yl methanol, which was used in the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:20][S:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[CH3:32])(=[O:23])=[O:22])[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:33]([O:35][C:36]1[C:37](=O)[C:38](=[O:43])[C:39]=1[O:40]CC)[CH3:34]>C(O)CC>[CH2:33]([O:35][C:36]1[C:39](=[O:40])[C:38](=[O:43])[C:37]=1[NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:20][S:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[CH3:32])(=[O:23])=[O:22])[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[CH3:34]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cccc(N)c2)cc1)NS(=O)(=O)c1c(C)cc(C)cc1C
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCCO
Product: CCOc1c(Nc2cccc(-c3ccc(C[C@H](NS(=O)(=O)c4c(C)cc(C)cc4C)C(=O)OC)cc3)c2)c(=O)c1=O
Yield: 59 %

Procedure:
2 g of Methyl (2S)-3-(3′-amino[1,1′-biphenyl]-4-yl)-2-mesitylsulfonylamino-propanoate 12.1.2 were mixed with 0.75 g 3,4-diethoxy-3-cyclobuten-1,2-dion in 40 ml 1 propanol and refluxed for 20 h. Purification by flash chromatography (dichloromethane/acetic acid ethyl ester 10+1) yielded 1,5 g of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=4)[CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=4)[CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1)=[O:32]
Reactant: CSc1nccc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nccc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)n1
Yield: 107.4 %

Procedure:
1-(2-(Methylthio)pyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (91 mg, 0.251 mmol) was dissolved in methylene chloride (1 mL). At 0° C., 3-chloroperoxybenzoic acid (87 mg, 0.502 mmol) was added. 1 hour later, the reaction mixture was added to sodium bicarbonate aqueous solution and extracted with methylene chloride. The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. 1-(2-(Methylsulfinyl)pyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (102 mg) was yielded.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:41]([C:44]1[CH:54]=[CH:53][C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=1)=[C:42]=[O:43].C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:42]([NH:41][C:44]2[CH:54]=[CH:53][C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=2)=[O:43])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 137.9 %

Procedure:
To a solution of 181 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate and 0.114 mL of triethylamine and 2.7 mL of THF was added 117 mg of ethyl 4-isocyanatobenzoate at room temperature. The reaction vessel was tightly sealed, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, and a saturated aqueous sodium hydrogen carbonate solution was then added thereto, followed by extraction with chloroform. Then, the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 357 mg of ethyl 4-({[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}amino)benzoate as a crude product. ESI+: 636
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.O.S(=O)(=O)(O)[OH:27]>CCOCC.C1COCC1.C(OCC)(=O)C>[CH2:17]([N:14]1[CH2:13][CH2:12][CH:11]([C:10](=[O:27])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:16][CH2:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(O)O
Reactant: C(CCCc1ccccc1)=C1CCN(Cc2ccccc2)CC1
Agent: B
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-phenylbutylidene)-1-benzylpiperidine from Step C (4.37 g) in anhydrous ether (150 mL) under nitrogen with stirring was add 1M borane solution in THF (45 mL). The reaction was stirred for 3 h when water (2 mL) was added dropwise. The mixture was stirred a further 30 min and was then cooled in an ice bath. A solution of chromic anhydride (2.5 g), concentrated sulfuric acid (5.44 mL) and water (125 mL) was added dropwise with vigorous magnetic stirring over 5 min. After another 5 min, the ice bath was removed. After 1.5 h at rt, 0.5N sodium hydroxide and ether (400 mL each) were added and the mixture was stirred until the residue dissolved. The layers were separated and the aqueous layer was extracted twice with ether. The combined ether layers were washed with an aqueous EDTA solution, water and brine (100 mL each), dried over sodium sulfate and concentrated under reduced pressure to give a colorless gel. Flash chromatography on silica gel with 30-50% ethyl acetate in hexanes with 3% (v/v) TEA gave the title compound (1 g) as a colorless gel. Rf: 0.43 (30% ethyl acetate in hexanes with 3% (v/v) TEA).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:14][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:12])[F:1])=[N:9][CH:8]=1
Reactant: OCc1ccc(OC(F)F)nc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)Oc1ccc(CBr)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of (6-(difluoromethoxy)pyridin-3-yl)methanol (246 mg; 1.41 mmol) in anh. DCM (10 ml) was treated at rt with CBr4 (467 mg; 1.41 mmol), and with triphenylphosphine (369 mg; 1.41 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 15 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 5-(bromomethyl)-2-(difluoromethoxy)pyridine as an orange oil which was directly used for the next reaction.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2].[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>N1C=CC=CC=1>[C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:25](=[O:28])[CH2:26][CH3:27])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2]
Reactant: N#CC=C1CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Product: CCC(=O)NC[C@H]1CN(c2ccc(N3CCC(=CC#N)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
The mixture of (S)-N-{3-[4-(4-cyanomethylidene-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine (1.5 mmol), propionyl chloride (1.79 mmol) in 10 ml pyridine was stirred at room temperature for 3 hours. Evaporation of the solvent under vacuum and silica gel column chromatography afforded the titled compound in 52% yield.
Reaction SMILES: [Na].CO[CH:4](OC)[C:5](=[CH:8]O)[C:6]#[N:7].[C:12]([CH2:14][C:15](=[S:17])[NH2:16])#[N:13].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>Cl.C(N(CC)CC)C>[C:12]([C:14]1[C:15]([SH:17])=[N:16][CH:4]=[C:5]([C:6]#[N:7])[CH:8]=1)#[N:13]
Reactant: N#CCC(N)=S
Reactant: COC(OC)C(C#N)=CO
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCN(CC)CC
Product: N#Cc1cnc(S)c(C#N)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A suspension of the sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylonitrile (3.94 g, 23.86 mmol) in hydrochloric acid (20 ml, 0.5 M) is heated at 50° C. for 30 minutes. Excess hydrochloric acid is neturalized using triethylamine, before adding cyanoacetothioamide (2.39 g, 23.9 mmol) and a catalytic amound of benzyltrimethylammonium hydroxide. The mixture is stirred at room temperature for two hours, heated at 60° C. for 2 hours and then refluxed for 4 hours. Evaporation of the solvents leaves a solid that is purified on silicagel to yield 3,5-dicyano-2-marcaptopyridine.
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[CH3:18][NH:19][CH3:20].O.[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl.CC(C)=O>[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24].[Cl:17][C:14]1[CH:15]=[CH:16][C:11](/[C:4](/[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)=[CH:3]/[CH2:2][N:19]([CH3:20])[CH3:18])=[CH:12][CH:13]=1
Reactant: CNC
Reactant: ClCC=C(c1ccc(Cl)cc1)c1cccnc1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: CN(C)C/C=C(/c1ccc(Cl)cc1)c1cccnc1
Yield: 35 %

Procedure:
A solution of crude 3-chloro-1-(4-chlorophenyl)-1-(3-pyridyl)-1-propene (40 mmol) was added to dimethylamine (18.0 g, 400 mmol) in 25 ml methylene chloride at 10° C. After stirring at room temperature for 1.5 h 25 ml water were added, the phases separated and the solvent removed from the organic phase. The residue was taken up in ether and extracted with dilute hydrochloric acid to pH 4.5. The aqueous phase was made alkaline, extracted with ether and the solvent removed. The residual oil (6.8 g) was dissolved in acetone and one equivalent of oxalic acid in acetone was added. The precipitated oxalate was recrystallized twice from ethanol to give 5.1 g (35%) of pure product mainly (95%) containing the Z-isomer. M.p. 164°-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[BH4-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[OH:6])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(c1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 12.5 h
Yield: 76 %

Procedure:
To a solution of 3-bromobenzophenone (1.00 g, 4 mmol) in MeOH (15 mL) was added sodium borohydride (0.3 mL, 8 mmol) portionwise at rt and the suspension was stirred at rt for 1-24 h. The reaction was diluted slowly with water and extracted with CH2Cl2. The organic layer was washed successively with water, brine, dried over Na2SO4, and concentrated to give the title compound as oil (0.8 g, 79%), which was used in the next reaction without further purification. MS (ESI, pos. ion) m/z: 247.1 (M-OH).
Reaction SMILES: Cl.[SH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:15][CH2:16][N:17]=[C:18]=[S:19].[CH3:20][S:21]([OH:24])(=[O:23])=[O:22]>O1CCCC1>[CH3:20][S:21]([OH:24])(=[O:23])=[O:22].[SH:2][CH:3]1[CH2:6][N:5]([C:18]2[S:19][CH2:15][CH2:16][N:17]=2)[CH2:4]1
Reactant: S=C=NCCCl
Reactant: SC1CNC1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: SC1CN(C2=NCCS2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
To a solution of 63.3 mg of 3-mercaptoazetidine hydrochloride (12) obtained in the above Example 10 dissolved in 1.0 ml of dried tetrahydrofuran, there was added 0.07 ml of triethylamine in the stream of nitrogen at a room temperature, and the resulting solution was stirred for 30 minutes. To this solution, there was added dropwise a solution of 70.3 mg of 2-chloroethylisothiocyanate dissolved in dried tetrahydrofuran, and the resulting solution was further stirred for one hour. After the reaction liquid was cooled to 0° C., 0.04 ml of methanesulfonic acid was added dropwise, and the resulting solution was stirred for 30 minutes, and, then, the solvent was evaporated in a vacuum. To the obtained residue, there was added 1.0 ml of dried methanol, and the resulting solution was subjected to heating and reflux for one hour, and, then, the solvent was evaporated in a vacuum. The obtained residue was separated and purified by thin-layer chromatography, and, thus, there was obtained 53.4 mg (yield: 39.2%) of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine methanesulfonate (13) in the form of colorless oily matter.
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1>C(Cl)Cl.C1COCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[N:15]2[CH2:16][C:13](=[C:4]([C:5]3[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([F:11])[CH:10]=3)[CH2:3][OH:2])[CH2:14]2)=[CH:26][CH:27]=1
Reactant: COC(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2.11 g (4.45 mmol) of methyl{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetate in 40 mL of hexanes and 40 mL of CH2Cl2 was added a solution of 26.7 mL (26.7 mmol) of DIAL-H (1M solution in THF), followed by stirring for 1 h at −78° C. The reaction mixture was warmed to rt for 1.5 h, quenched by addition of 8 g of sodium sulfate decahydrate, and stirred for 1 h at rt. The quenched reaction was filtered and the organic layer was concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid. 1NMR (CDCl3) δ 3.99 (s, 2H), 4.03 (s, 21), 4.35 (s, 2H), 4.54 (s, 1H), 6.70-6.80 (m, 3H), 7.306-7.40 (m, 8H); Mass Spectrum: m/e=446 (M+1 35Cl, 35Cl) and 448 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:13][CH3:14].[C:19]([C:23]1[O:24][C:25]([CH3:30])=[C:26]([CH2:28]Cl)[N:27]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:28][C:26]2[N:27]=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:24][C:25]=2[CH3:30])=[CH:8][C:7]=1[CH2:13][CH3:14]
Reactant: CCO[C@@H](Cc1ccc(O)cc1CC)C(=O)OC
Reactant: Cc1oc(C(C)(C)C)nc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(C(C)(C)C)oc2C)cc1CC)C(=O)OC

Procedure:
In analogy to the procedure described in example 46 c], (2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl ester was reacted with 2-tert-butyl-4-chloromethyl-5-methyl-oxazole (example 1, step b]) in the presence of cesium carbonate and potassium iodide to yield (S)-3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-2-ethyl-phenyl]-2-ethoxy-propionic acid methyl ester as colorless liquid.