Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(=O)c1ccccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(=O)c1ccccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 23 h
Yield: 91.8 %

Procedure:
A mixture of 2'-hydroxypropiophenone (25.8 g), benzyl chloride (21.8 g), sodium iodide (2.6 g), potassium carbonate (23.8 g) and dry dimethylformamide (260 ml) was heated with stirring at 80° C. for 23 hours. The mixture was cooled and filtered and the filtrate was concentrated under reduced pressure. The residue was extracted with ether and the extract was washed with water, 1N aqueous sodium hydroxide, water, 10% hydrochloric acid, aqueous sodium hydrogen carbonate and aqueous sodium chloride in that order, dried, and concentrated to dryness to give 2'-benzyloxypropiophenone (37.9 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(Cl)([Cl:17])=O>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1

Procedure:
1.5 g of 4-fluoro-3-trifluoromethylbenzoic acid, 0.65 ml of thionyl chloride and two drops of DMF are heated under reflux for 12 h in 17 ml of toluene and the mixture is subsequently concentrated and used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].IC.CC(OC)(C)C>CN(C=O)C>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: CI
Product: COC(=O)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To a 100 mL round bottom flask was added 3-bromo-2-fluorobenzoic acid (5.00 g, 22.8 mmol, Oakwood), potassium carbonate (3.17 g, 22.9 mmol), and DMF (30 mL). Iodomethane, 2 M in MTBE (11.6 ml, 23.2 mmol) was added and the reaction mixture was stirred at RT for 16 hours. The reaction was filtered and the filtrate concentrated was in vacuo. The resulting brown crude residue was taken up with EtOAc and again filtered and concentrated to give methyl 3-bromo-2-fluorobenzoate (4.76 g, 20.4 mmol, 89.5% yield), as a brown syrup that was used in the Step 2 without further purification.
Reaction SMILES: O=[C:2]([CH2:7][CH2:8][C:9]([O:11]C)=O)[C:3]([O:5][CH3:6])=[O:4].[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>CO>[OH:11][C:9]1[C:8]([CH2:7][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[N:19][C:14]2[C:13]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: COC(=O)CCC(=O)C(=O)OC
Reactant: Nc1ccccc1N
Solvent: CO
Product: COC(=O)CCc1nc2ccccc2nc1O
Reaction time: 8 h
Yield: 101.2 %

Procedure:
Dimethyl 2-ketoglutarate (3.75 g) and o-phenylenediamine (2.5 g) were dissolved in methanol (30 ml), and the mixture was stirred overnight. The precipitated crystals were recovered by filtration and washed with water and methanol to obtain 5.06 g of methyl 3-(3-hydroxyquinoxaline-2-yl)propanoate Yield: 94%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.C([OH:31])(C)(C)C>[Zn]>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:31])[CH2:9]2
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]ccc2c1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)O
Agent: [Zn]
Product: COC(=O)[C@@H](Cc1ccc2c(c1)CC(=O)N2)NC(=O)OCc1ccccc1
Temperature: 27.5 °C
Reaction time: 3.5 h
Yield: 41 %

Procedure:
PyHBr3 (1.28 g, 4.02 mmol) was added in small portions over 30 min to a solution of (R)-2-benzyloxycarbonylamino-3-(1H-indol-5-yl)-propionic acid methyl ester (0.47 g, 1.34 mmol) in t-butanol (10 mL) while the reaction temperature was maintained between 25-30° C. The resulting mixture was stirred at room temperature for 3.5 h. The solvent was removed in vacuo, and the residue was extracted with ethyl acetate (2×). The combined organic phases were washed with brine and dried over sodium sulfate. After filtration, solvents were removed and the residue was azeotropically dried with anhydrous ethanol. The residue was dissolved in glacial acetic acid (10 mL) and zinc powder (0.88 g, 13.4 mmol) was added. The mixture was stirred at room temperature overnight. After the acetic acid was removed in vacuo, the residue was purified by flash chromatography on silica gel using ethyl acetate/hexanes [(1:3) first and then (3:2)] as eluent to afford the title compound as a white solid (41% for 2 steps).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[OH:20])[C:5]([NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[N:13][NH:14]2)=[CH:10][CH:9]=1)=[O:6].[N:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])=[C:22]=S.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([NH:7][C:5]([C:4]3[CH:17]=[CH:18][C:19]4[O:20][C:22]([NH:21][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:31])([F:32])[F:33])=[N:1][C:2]=4[CH:3]=3)=[O:6])[CH:16]=2)[CH:12]=[N:13]1
Reactant: Nc1cc(C(=O)Nc2ccc3cn[nH]c3c2)ccc1O
Reactant: FC(F)(F)c1ccccc1N=C=S
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2cn[nH]c2c1)c1ccc2oc(Nc3ccccc3C(F)(F)F)nc2c1
Temperature: 25 °C

Procedure:
A solution of the aminophenol (0.5 mmol) from above in DMF (2 mL) was added with 1-isothiocyanato-2-trifluoromethylbenzene (0.6 mmol) and DIEA (1 mmol). The reaction mixture was subjected to microwave irradiation at 120° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL). The solid formed was collected by filtration, washed with water, and dried in vacuo. The crude product was purified on a silica gel column chromatography using MeOH/DCM as eluent to provide 2-(2-trifluoromethylphenylamino)-benzooxazole-5-carboxylic acid (1H-indazol-6-yl)-amide, obtained as a yellow solid. MS: m/z 438 (M+H)+.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([S:11][CH3:12])[N:5]=1>ClCCl>[Cl:3][C:4]1[N:5]=[C:6]([S:11][CH3:12])[N:7]=[C:8]([NH:1][NH2:2])[CH:9]=1
Reactant: NN
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: ClCCl
Product: CSc1nc(Cl)cc(NN)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
Referring to Scheme 2, anhydrous hydrazine (164 mg, 162 μl, 5.1 mmol) and dichloromethane (3 ml) were cooled to −78° C. 4,6-Dichloro-2-(methylthio)pyrimidine (1 g, 5.1 mmol) was slowly added. The mixture was allowed to stir for 10 minutes then the bath was replaced with an ice bath and the solution allowed to slowly reach 0° C. The precipitate was filtered and washed with DCM. 1-(6-Chloro-2-(methylthio)pyrimidin-4-yl)hydrazine (624 mg, 64%) was obtained. [M+H] calc'd for C5H7ClN4S, 191; found, 191.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:19](=[O:20])[CH2:18][N:17]([CH2:21][C@H:22]([NH:30]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[C@@H:23]2[CH2:27][C@@H:26]([CH3:28])[C:25](=[O:29])[O:24]2)[C:16]([CH3:44])([CH3:43])[CH2:15]1.C1(S)C=CC=CC=1.C(=O)(O)[O-].[Na+].[C:57](OC(OC(C)(C)C)=O)([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58].N[C@H]([C@@H]1C[C@@H](C)C(=O)O1)CN1C(C)(C)CN(C2C=CC=CC=2Cl)C(=O)C1>C(#N)C.[Cl-].[Na+].O.C(OCC)(=O)C.O>[C:60]([O:59][C:57](=[O:58])[NH:30][C@H:22]([C@@H:23]1[CH2:27][C@@H:26]([CH3:28])[C:25](=[O:29])[O:24]1)[CH2:21][N:17]1[CH2:18][C:19](=[O:20])[N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[Cl:7])[CH2:15][C:16]1([CH3:43])[CH3:44])([CH3:63])([CH3:62])[CH3:61]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: C[C@@H]1C[C@@H]([C@@H](N)CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)OC1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: C[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reaction time: 1 h
Yield: 84.2 %

Procedure:
925 mg of cesium carbonate (2.84 mmol) was added to a solution of 1.34 g of N-{(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (76h) (2.37 mmol) and 0.51 ml of thiophenol (content: 95%) (4.74 mmol) in acetonitrile (12 ml) under a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature for one hour. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=20/1-10/1). 208 mg of sodium bicarbonate (2.47 mmol) and 538 mg of di-t-butyl dicarbonate (2.47 mmol) were added to a solution of 4-{(S)-2-amino-2-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}1-(2-chlorophenyl)-5,5-dimethylpiperazin-2-one obtained above in ethyl acetate (10 ml)-water (10 ml), and the mixture was stirred at room temperature for two hours. Brine was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=2/1-1/1) to obtain 958 mg of the title compound (yield: 84%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:8][C@@H:9](OS(C3C=CC(C)=CC=3)(=O)=O)[C@H:5]2[O:4][CH2:3]1.[CH3:28][S-:29].[Na+].[Cl-].[NH4+]>CC(N(C)C)=O>[OH:1][C@@H:2]1[C@H:6]2[N:7]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:8][C@H:9]([S:29][CH3:28])[C@H:5]2[O:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reactant: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS[C@H]1CN(C(=O)OC(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A stirred solution of tosylate (35b) (250 mg, 0.63 mmol) and sodium thiomethoxide [CAS 5188-07-8] (88 mg, 1.25 mmol) in 3 ml of DMA was heated under an atmosphere of argon in a sealed pressure vessel at 90° C. for 2 hours. The mixture was then allowed to cool to ambient temperature then an aqueous saturated solution of ammonium chloride (10 mL) was added. The aqueous phase was extracted with tert-butyl methyl ether (3×7 ml). The organic phase was dried (MgSO4), filtered and reduced in vacuo to leave an oil. Flash chromatography over silica, eluting with diethyl ether:pentane 2:1 gave thiomethylether (54) as colourless oil (0.152 g, 88%). TLC (Rf=0.29, Et2O:pentane 2:1), HPLC-MS 220.1 [M+2H−tBu]+, 573.2 [2M+H]+; δH (500 MHz, CDCl3) mixture of rotamers 1:1; 1.46 (4.5H, s, CCH3), 1.49 (4.5H, s, CCH3), 2.16 (3H, s, SCH3), 3.20 (1H, brs, BocNCH2), 3.47-4.05 (4H, m, OCH2CHOH, BocNCH2 and CHSCH3), 4.24-4.45 (2H, m, BocNCH and OCH2CHOH), 4.63 (1H, s, OCHCHSCH3).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:3]([OH:22])[CH2:4][N:5]1[C@H:14]([C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][C@H:12]2[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1.[CH2:30]([O:37][C:38]([NH:40][C@H:41]([C:46](O)=[O:47])[CH2:42][C:43](=[O:45])[NH2:44])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[CH2:30]([O:37][C:38]([NH:40][C@H:41]([C:46]([NH:1][C@@H:2]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@H:3]([OH:22])[CH2:4][N:5]1[C@H:14]([C:15]([NH:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][C@H:12]2[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1)=[O:47])[CH2:42][C:43](=[O:45])[NH2:44])=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 47.8 %

Procedure:
A solution of 561 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 372 mg of N-(benzyloxycarbonyl)-L-asparagine in 20 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 189 mg of hydroxybenzotriazole, 161 mg of N-ethylmorpholine and 317 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 16 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution. The solvent was removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution to give 434 mg of 2-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid from methanol/diethyl ether; MS: m/e 650 [M+H]+, NMR: δ (d4CH3OH, 400 MHz):
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:8][C:7]=1[Cl:19].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[Cl:19][C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:11]([Cl:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:31])([F:20])[F:32])=[CH:27][N:26]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Reactant: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 10.4 %

Procedure:
To a mixture of 0.96 g of 4-(3-aminopropyloxy)-3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)benzene, 0.53 g of 5-(trifluoromethyl)-2-pyridinecarboxylic acid, 0.37 g of triethylamine and 10 ml of chloroform was added 0.64 g of WSC hydrochloride, while stirring at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.15 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(5-(trifluoromethyl)picolinamido)propoxy)benzene (10% yield), m.p., 55.1° C.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH3:9][S:10][CH3:11].[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:41][CH2:40][C:27]3([C:32]4=[CH:33][CH:34]=C[N:31]4[C:30]4[CH:36]=[CH:37][CH:38]=[CH:39][C:29]=4[O:28]3)[CH2:26][CH2:25]2)=[O:23])=[CH:18][C:17]=1[CH3:42])([CH3:14])[CH3:13]>ClCCl.C1(C)C=CC=CC=1>[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:41][CH2:40][C:27]3([O:28][C:29]4[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=4[N:31]4[C:9]([S:10][CH3:11])=[CH:34][CH:33]=[C:32]34)[CH2:26][CH2:25]2)=[O:23])=[CH:18][C:17]=1[CH3:42])([CH3:14])[CH3:13]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1OC(C)C
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CSc1ccc2n1-c1ccccc1OC21CCN(C(=O)c2ccc(OC(C)C)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110.3 %

Procedure:
A solution of 1-chloropyrrolidine-2,5-dione (92 mg, 0.70 mmol) in dry dichloromethane (3.2 mL) was added dropwise at −10° C. to a solution of methylsulfanylmethane (82 μL, 1.1 mmol) in dry dichloromethane (800 μL) over a period of 5 minutes. The reaction was allowed to warm to room temperature and was stirred for 30 minutes. The mixture was then cooled to −55° C. and a solution of (4-isopropoxy-3-methyl-phenyl)-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl-methanone (210 mg, 0.49 mmol) in dry dichloromethane (800 μL) was added dropwise. The cooling bath was removed and the mixture was gradually warmed up to room temperature and was stirred overnight. The solvent was removed under vacuum and the pink residue that was obtained was dissolved in dry toluene (7 mL) and was heated at 50° C. for 5 minutes. The solvent was removed to afford (4-isopropoxy-3-methylphenyl)(1-(methylthio)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (250 mg, 78%). ESI-MS m/z calc. 462.2. found 463.5 (M+1)+; Retention time: 2.43 minutes (3 min run).
Reaction SMILES: [CH2:1]([C@@:4]1(C)[CH2:9][C@H:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[C@@H:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C@@H:25]([CH2:31][CH3:32])[CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:5]1=[O:33])C=C.O.I([O-])(=O)(=O)=O.[Na+].CC[O:44][C:45]([CH3:47])=[O:46]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:6]([C@@H:25]([CH2:31][CH3:32])[CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:5](=[O:33])[C@:4]([CH2:47][C:45]([OH:44])=[O:46])([CH3:1])[CH2:9]2)[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: CCOC(C)=O
Reactant: C=CC[C@@]1(C)C[C@H](c2cc(F)cc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CS(C)(=O)=O)C1=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CC[C@@H](CS(C)(=O)=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cc(F)cc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylsulfonyl)butan-2-yl)piperidin-2-one (Example 395, Step B, 58 mg, 0.110 mmol) in acetonitrile (1.0 mL), EtOAc (1.0 mL), and water (1.5 mL) was added ruthenium(III) chloride hydrate (0.55 mg, 2.42 μmol) and sodium periodate (144 mg, 0.672 mmol). After 2 hours, the mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography on silica gel (eluent: 10% MeOH/DCM) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13]C1C=C(C=CC=1)C(OO)=O.P(Cl)(Cl)(Cl)=O>C(Cl)Cl.ClCCCl>[Cl:13][CH2:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cccnc1C
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cccnc1CCl
Reaction time: 72 h
Yield: 11 %

Procedure:
A solution of 9 g of ethyl 2-methylnicotinate in 250 mL methylene chloride is stirred at room temperature and 32 g of 80% metachloroperoxybenzoic acid is added in one portion. The resulting solution is stirred for three days. The precipitated solid is filtered off, and the filtrate is washed with cold, dilute aqueous sodium hydroxide, dried, and concentrated in vacuo to afford the crude N-oxide. This material is digested in 75 mL of 1,2-dichloroethane; 15 mL of phosphorous oxychloride is added, and the solution is heated at reflux overnight. The solution is concentrated in vacuo, and the residue is taken up in methylene chloride and neutralized with aqueous sodium acetate. The organic phase is dried, concentrated in vacuo, and the residue is chromatographed on silica gel using hexane-ethyl acetate mixtures to afford 1.2 g of the title product as an oil having
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:11]2[CH2:16][CH2:15][C@:14]([CH2:23][CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:25])[CH2:9][CH3:10])=[CH:4][CH:3]=1.Br[C:27]1[CH:28]=[CH:29][C:30](=[O:35])[N:31]([CH2:33][CH3:34])[CH:32]=1>>[CH2:23]([C@@:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][C:12](=[O:25])[N:11]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[CH:29][C:30](=[O:35])[N:31]([CH2:33][CH3:34])[CH:32]=3)=[CH:3][CH:4]=2)[CH2:9][CH3:10])[CH2:16][CH2:15]1)[CH3:24]
Reactant: CCn1cc(Br)ccc1=O
Reactant: CC[C@@H](c1ccc(Br)cc1)N1CC[C@](CC)(c2ccccc2)OC1=O
Product: CC[C@@H](c1ccc(-c2ccc(=O)n(CC)c2)cc1)N1CC[C@](CC)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 459 Steps 3 and 4 using 5-bromo-1-ethylpyridin-2(1H)-one in Step 4. LC-MS Method 1 tR=1.68 min, m/z=445 (M+1).
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.C[C:21]1[CH:25]=[CH:24][O:23][C:22]=1[CH2:26][C:27]([NH:29][C:30]1[N:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=1)=[O:28]>C(Cl)Cl.O>[S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:36]([C:33]3[CH:32]=[CH:31][C:30]([NH:29][C:27]([C:26]4[CH:25]=[CH:24][O:23][C:22]=4[CH3:21])=[O:28])=[N:35][CH:34]=3)=[O:37])[C:4]=2[CH:3]=[CH:2]1
Reactant: Cc1ccoc1CC(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1cc2c(s1)CCCCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1occc1C(=O)Nc1ccc(C(=O)N2CCCCc3sccc32)cn1

Procedure:
A solution of 2 mmol of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine, 5 mmol of N,N-diisopropylethylamine and 2.2 mmol of 6-[(3-methyl-2-furanylacetyl)amino]pyridine-3-carbonyl chloride in 10 ml of CH2Cl2 is stirred at room temperature for 16 hours. The mixture is diluted with 50 ml of CH2Cl2 and 25 ml of water and the organic layer separated. The organic layer is washed with H2O, 1N NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue is chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:20][O:21][P:22]([O-:25])[O:23][CH3:24].C(NCCCC)CCC.CCCCCC>CCOCC>[CH3:19][Si:2]([CH3:1])([CH3:18])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:11])([P:22](=[O:25])([O:23][CH3:24])[O:21][CH3:20])[P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COP([O-])OC
Reactant: COP(=O)(OC)C(=O)Cc1cccc([Si](C)(C)C)c1
Solvent: CCCCNCCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COP(=O)(OC)C(O)(Cc1cccc([Si](C)(C)C)c1)P(=O)(OC)OC
Yield: 65.3 %

Procedure:
To a solution of dimethyl m-trimethylsilylphenylacetylphosphonate (1.63 g, 5.0 mmol) in Et2O (10 cm3) was added a solution of dimethylphosphite (0.83 g, 7.5 mmol), dibutylamine (0.32 g, 2.5 mmol) and hexane (10 cm3) at 0° C. A white solid began to form after a few minutes. After 20 min the mixture was filtrated to give the title compound (1.34 g, 65%) as a white solid. Recrystallization was achieved by adding water (9.5 cm3) to a solution of the title compound (0.50 g) in acetic acid (0.5 cm3) and then leaving the resulting mixture for several days in the refrigerator. Filtration afforded the bisphosphonate (0.33 g, 66%) as white crystals.