Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[C:27]([F:30])([F:29])[F:28].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[C:27]([F:30])([F:29])[F:28])[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(Cl)cc2C(F)(F)F)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3C(F)(F)F)n(CCCO)c12
Temperature: 50 °C
Reaction time: 15 h
Yield: 98.6 %

Procedure:
A mixture of the resulting thiourea (22.0 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.49 g, 44.3 mmol), and triethylamine (6.2 mL) in tetrahydrofuran (150 mL) was stirred at 50° C. for 15 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with n-hexane to give methyl 4-chloro-2-{[4-chloro-2-(trifluoromethyl)phenyl]amino}-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate as a brown powder (20.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[C:18]1(=[O:25])[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1.C(N(CC)CC)C>ClCCl.CN(C)C=O.[C-]#N.[Zn+2].[C-]#N.CC([O-])=O.CC([O-])=O.[Cu+2].C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:19]1[C:20](=[O:24])[CH2:21][CH2:22][CH2:23][C:18]1=[O:25])=[O:11]
Reactant: O=C1CCCC(=O)C1
Reactant: O=C(O)Cc1ccccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCCC(=O)C1C(=O)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.5 %

Procedure:
To a solution of 17.1 grams (g) (0.1 mole) of (2-chlorophenyl) acetic acid in 100 milliliters (ml) of dichloromethane and 0.5 ml of dimethylformamide was added 19.0 g (0.15 mole) of oxalyl chloride dropwise over a 30 minute period. Evolution of gas commenced and lasted for approximately 30 minutes, after which the excess liquids were removed in vacuo. To the residue was added 100 milliliters (ml) of acetonitrile and 12.0 g (0.1 mole) of zinc cyanide, and the mixture was stirred for 15 minutes at room temperature. Thereafter, 11.2 g (0.1 mole) of 1,3-cyclohexanedione was added, followed by the dropwise addition of 15.0 g (0.148 mole) of triethylamine over a five minute period. The exothermic reaction reached approximately 50° C., after which it subsided. The mixture was heated at reflux for approximately one hour, then cooled to room temperature and the acetonitrile was removed in vacuo. To the residue was added 2N hydrogen chloride (to decompose the zinc salts), and ethyl ether. The various layers were separated, and the organic layer was washed with 5% potassium carbonate. The aqueous layer was acidified and extracted with dichloromethane three times. The dichloromethane layer was dried over magnesium sulfate, and the excess dichloromethane was roto-evaporated off. The crude product that was obtained was then stirred with a 5% Cu(OAc)2 solution. The blue copper complex that resulted was filtered, and then decomposed with 6N HCl. The acidic solution was extracted with dichloromethane. After drying over MgSO4, the dichloromethane was removed in vacuo to afford 1.2 g of a brown semi-solid which was identified as the subject compound.
Reaction SMILES: OC1C=CC(C2SC([C:13]3C=C[C:16]([C:17]([O:19][CH3:20])=O)=[CH:15][CH:14]=3)=NN=2)=CC=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][C:33]([C:35]3[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=3)=[N:32][N:31]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].BrCCCCCBr.Cl.C[O-].[Na+]>O1CCCC1.O.CO.CN(C)C=O>[CH3:20][O:19][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[S:34][C:33]([C:35]3[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=3)=[N:32][N:31]=2)=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccc(-c2nnc(-c3ccc(O)cc3)s2)cc1
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccc(O)cc3)s2)cc1
Agent: BrCCCCCBr
Agent: C[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COCCCCCOc1ccc(-c2nnc(-c3ccc(C(=O)O)cc3)s2)cc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a suspension of a mixture of methyl 4-[5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoate and 4-[5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid (3.12 g), potassium carbonate (22.07 g) and N,N-dimethylformamide (15 ml) was added 1,5-dibromopentane (15 ml) and the mixture was stirred at 100° C. (bath temperature) for 5 hours. The resulting mixture was neutralized by 0.1N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with n-hexane. The solid was collected by filtration and dried to give a crude powder (3.71 g). To the crude powder (2.11 g) was added methanol (100 ml) and sodium methoxide (28% in methanol) (10 ml), and refluxed for 2 hours. Then to the reaction mixture was added sodium methoxide (28% in methanol) (5 ml) and refluxed for 1.5 hours. After cooling, the reaction mixture was added to water and tetrahydrofuran, stirred overnight and adjusted to pH 2 with 4N hydrochloric acid. The resulting precipitate was collected by filtration, washed with acetonitrile and dried under reduced pressure to give 4-[5-[4-(5-methoxy-n-pentyloxy) phenyl]-1,3,4-thiadiazol-2-yl]benzoic acid (1.34 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26](=[O:30])[N:27]([CH3:29])[CH3:28])([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:29][N:27]([CH3:28])[C:26]([C:23]([NH:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:31])([CH3:32])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)([CH3:24])[CH3:25])=[O:30]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)N(C)C)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 6.1 %

Procedure:
A mixture of 2-[3-(1-dimethylcarbamoyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.8 g, 1.8 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 50° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(1-dimethylcarbamoyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (45 mg, 6%) as a white solid: LC/MS m/e calcd for C24H31N3O3 (M+H)+: 410.53, observed: 410.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].C[Mg]Cl.[CH2:15]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:30](Cl)=[O:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:15]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:30](=[O:31])[CH:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])[C:8](=[O:9])[CH3:10])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: O=C(Cl)C1CCCN1C(=O)OCc1ccccc1
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)C(C(=O)OC(C)(C)C)C(=O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
A solution of tert-butylacetoacetate (7.90 g, 50.0 mmol) in anhydrous THF (50 mL) was cooled to 4° C. (ice-water bath) prior to dropwise addition of methylmagnesium chloride (16.3 mL of a 3.00M solution in THF, 50.0 mmol) at such a rate that the temperature did not exceed 10° C. After the addition was complete the cooling bath was removed. When the temperature reached 15° C., 2-chlorocarbonyl-pyrrolidine-1-carboxylic acid benzyl ester (6.60 g, 25.0 mmol) was added dropwise over 1 h then warmed to rt and stirred for 12 h. The reaction was quenched with saturated aqueous NH4Cl (30 mL). The organic layer was separated from the solid residues and concentrated under vacuum to give 9.74 g (quant.) of 2-(2-tert-butoxycarbonyl-3-oxo-butyryl)-pyrrolidine-1-carboxylic acid benzyl ester as a yellow oil. The product was used directly in the subsequent step without further purification.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[OH:11][CH:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][N:19]=2)[C:14](=[O:21])[N:13]1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1.O>N1C=CC=CC=1>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([N:13]2[CH:12]([O:11][C:2]([O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:3])[C:20]3[C:15](=[N:16][CH:17]=[CH:18][N:19]=3)[C:14]2=[O:21])=[N:23][CH:24]=1
Reactant: Cc1ccc(N2C(=O)c3nccnc3C2O)nc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(N2C(=O)c3nccnc3C2OC(=O)Oc2ccccc2)nc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
Phenyl chloroformate (16.4 g.) is run, over the course of 10 minutes, at a temperature of about 20° C., into a suspension of 5-hydroxy-6-(5-methylpyrid-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (8.47 g.) in anhydrous pyridine (110 cc.). The reaction mixture is stirred for 3 hours at a temperature of about 20° C. and is then cooled to a temperature of about 5° C. Water (350 cc.) is then added over the course of 15 minutes. The insoluble product is filtered off, washed with water (4×50 cc.), acetonitrile (2×25 cc.) and diisopropyl ether (2×30 cc.). After drying, 6-(5-methylpyrid-2-yl)-7-oxo-5-phenoxycarbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (11.8 g.), which melts at 176° C., is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C.[CH3:24][O:25][CH2:26]Cl>O1CCCC1>[CH3:24][O:25][CH2:26][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: CC(C)=CCc1cc(C=O)ccc1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOc1ccc(C=O)cc1CC=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Then, 7.0 g of the so-obtained 4-hydroxy-3-(3-methyl-2-butenyl)benzaldehyde was dissolved in770 ml of tetrahydrofuran, and 19.25 g of N,N-diisopropylethylamine was added to the solution and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction liquid was cooled to 0° C. and 7.0 ml of chloromethyl methyl ether was dropped into the reaction liquid, and the mixture was stirred at room temperature overnight. Then, the reaction liquid was poured into ice water, and the organic layer was extracted with ether, washed with water, dried with anhydrous sodium sulfate, and filtered. The obtained residue was subjected to the column chromatography (260 g of 200-400 mesh Kieselgel 60, hexane/ethyl acetate=6/1, 0.4 kg/cm2), fractions of 50 ml were recovered in sequence, and the 14th to 24th fractions were combined to obtain 7.85 g (yield=91.1%) of 4-methoxymethoxy-3-(3-methyl-2-butenyl)benzaldehyde in the form of a colorless liquid.
Reaction SMILES: CC(C)(OC(N[C@H](C(N[C@H](C([NH:26][C@@H:27]([CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[CH:28]([P:30]([O:35][CH2:36][CH3:37])([O:32][CH2:33][CH3:34])=[O:31])[OH:29])=O)CC(C)C)=O)CC1C=CC=CC=1)=O)C.[CH3:46][C:47]([CH3:72])([O:49][C:50]([NH:52][C@H:53]([C:69](O)=[O:70])[CH2:54][C:55]1[N:59]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:58]=[N:57][CH:56]=1)=[O:51])[CH3:48].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:46][C:47]([CH3:48])([O:49][C:50]([NH:52][C@H:53]([C:69]([NH:26][C@@H:27]([CH2:38][CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1)[CH:28]([P:30]([O:35][CH2:36][CH3:37])([O:32][CH2:33][CH3:34])=[O:31])[OH:29])=[O:70])[CH2:54][C:55]1[N:59]([CH2:60][O:61][CH2:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:58]=[N:57][CH:56]=1)=[O:51])[CH3:72]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cncn1COCc1ccccc1)C(=O)O
Reactant: CCOP(=O)(OCC)C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(OCC)C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cncn1COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Compound B from Example 2 (1.47 g, 4.46 mmol) was added to a solution of [(1,1-dimethylethoxy)carbonyl]-3-[(phenylmethoxy)methyl]-L-histidine (T. Brown and J. H. Jones, Journal of Chemical Society, Chemical Communications (1981), 648) in tetrahydrofuran (22 mL) and cooled to 0° C. 1-Hydroxybenzotriazole hydrate (682 mg, 4.46 mmol), N,N-diisopropylethylamine (854.5 μl, 4.9 mmol) and dicyclohexylcarbodiimide (920 mg, 4.46 mmol) were added sequentially. After 16 hours at 25° C., the reaction mixture was filtered and concentrated. The residue was dissolved in ethyl acetate (60 mL), washed sequentially with saturated aqueous sodium hydrogen carbonate (2×40 mL), saturated aqueous sodium chloride (40 mL), dried (Na2HSO4) and concentrated. Repeated purifications by column chromatography of the crude product (2.9 g) yielded 2.03 g (70.2%) of pure title A compound.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([Cl:9])([Cl:8])[C:4]([Cl:11])([Cl:10])[S:3]1.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:24])C=1.ClC1C=C(C=CC=1)C(O)=O>C(=O)=O>[CH3:1][N:2]1[C:6](=[O:7])[C:5]([Cl:8])([Cl:9])[C:4]([Cl:10])([Cl:11])[S:3]1=[O:24]
Reactant: CN1SC(Cl)(Cl)C(Cl)(Cl)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Product: CN1C(=O)C(Cl)(Cl)C(Cl)(Cl)S1=O
Temperature: 25 °C

Procedure:
To a solution of 2.55g. (0.01 mole) of 2-methyl-4,4,5,5-tetrachloro-3-isothiazolidinone in 10 ml. of chloroform at 0° is added a solution of 2.03g. (0.01 mole) of m-chloroperbenzoic acid (85% Technical) in 60 ml. of chloroform. The mixture is allowed to warm to room temperature and stand over a weekend. The solution is cooled in dry ice. White solid (m-chlorobenzoic acid) separates (0.91g.) and is removed by filtration. The filtrate is washed in a separatory funnel with 50 ml. of water containing 0.4g. of sodium bicarbonate. The chloroform solution is separated and dried over magnesium sulfate. Evaporation gives 2.54g. of crude product as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:16]2([F:29])[F:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2([F:29])[F:28])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(F)(F)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: FC1(F)CNCCC1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.9 %

Procedure:
To a solution of t-butyl 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine-1-carboxylate (5.2 g, 12.9 mmol) in MeOH (100 mL) was added 4 M HCl/dioxane (32.2 mL, 130 mmol) and the reaction mixture was stirred at rt for 5 h. The mixture was then evaporated under reduced pressure, and the residue was diluted with a saturated sodium bicarbonate solution and extracted with 200 mL of ethyl acetate. The layers were separated and the organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to preparative HPLC (method C) to afford 2.5 grams (63%) of racemic 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine. LCMS (method F) RT 2.044 min, m/z 304 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.31-7.48 (m, 5H) 7.21 (d, J=8.53 Hz, 2H) 6.98 (d, J=9.04 Hz, 2H) 5.10 (s, 2H) 3.05-3.20 (m, 2H) 2.98 (d, J=13.05 Hz, 1H) 2.74-2.87 (m, 1H) 2.60 (t, J=11.55 Hz, 1H) 1.88-2.00 (m, 4H) 1.72 (d, J=13.05 Hz, 1H), 19F NMR (377 MHz, DMSO-d6) δ-102.276, -102.900, -115.135, -115.759.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=2[N:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: CCc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CC[O-].[Na+].[N+:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH2:16](P(=O)(OCC)OCC)[P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>CO>[CH2:19]([O:18][P:17]([CH:16]=[CH:12][C:11]1[CH:14]=[CH:15][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=1)(=[O:24])[O:21][CH2:22][CH3:23])[CH3:20]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(C=Cc1ccc([N+](=O)[O-])cc1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium ethylate (4.95 g, 72.8 mmol) is added to a solution of 4-nitrobenzaldehyde (10 g, 66.2 mmol) in 200 ml of methanol, and tetraethyl methylenediphosphonate (21 g, 72.8 mmol) is then added dropwise. After 2 h of stirring at room temperature, a further 0.43 g of sodium ethylate and 2 g of tetraethyl methylene diphosphonate are added. After 15 min of stirring at room temperature, the ethanol is evaporated off under vacuum and the residue is bipartitioned in a water/ethyl acetate mixture. The organic phase is washed with water, then dried (MgSO4) and evaporated under vacuum to give the expected product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[NH:53]1[CH:57]=[C:56]([C:58](O)=[O:59])[CH:55]=[N:54]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:58]([C:56]2[CH:57]=[N:53][NH:54][CH:55]=2)=[O:59])[CH2:25]1
Reactant: O=C(O)c1cn[nH]c1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CN(C(=O)c2cn[nH]c2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 49 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 1H-pyrazole-4-carboxylic acid as the starting materials in 49% yield. LCMS for C26H25ClN9O2 (M+H)+: m/z=530.0.
Reaction SMILES: C1(CC([NH:10][C@@H:11]2[C:37](=[O:38])[N:13]3[C:14]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)=[S:26])=[C:15]([CH2:18][CH2:19][O:20][C:21](=[O:24])[CH2:22][Cl:23])[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl.O.CO>[NH2:10][C@@H:11]1[C:37](=[O:38])[N:13]2[C:14]([C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[S:26])=[C:15]([CH2:18][CH2:19][O:20][C:21](=[O:24])[CH2:22][Cl:23])[CH2:16][S:17][C@H:12]12
Reactant: COc1ccc(COC(=S)C2=C(CCOC(=O)CCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(COC(=S)C2=C(CCOC(=O)CCl)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
In 50 ml of dry dichloromethane was dissolved 1.70 g (2.88 mM) of p-methoxybenzyl 7β-phenylacetamido-3-(2-chloroacetyloxy)ethylthio-3-cephem-4-carboxylate, and the solution was cooled to -50° C. To the solution were added 0.706 ml (8.64 mM) of pyridine and 1.196 g (5.76 mM) of phosphorus pentachloride, the reaction temperature of the mixture was raised to 20° C. for a period of one hour, and the mixture was stirred at the same temperature for one hour. Then, the reaction mixture was cooled to -50° C., 10 ml of dry methanol was added, and the temperature of the mixture was raised to 0° C. for a period of one hour. To the reaction mixture cooled to -5° C. was added 10 ml of water, and the mixture was stirred under ice-cooling for 40 minutes. The mixture was made neutral by addition of a saturated aqueous sodium bicarbonate solution, the organic layer was washed with a saturated aqueous sodium chloride solution (10 ml×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent, dichloromethane) to give 1.22 g of p-methoxybenzyl 7β-amino-3-(2-chloroacetyloxy)ethylthio-3-cephem-4-carboxylate.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].B1C2CCCC1CCC2.Cl[C:20]1[CH:25]=[C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[N:23]=[C:22]([NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[N:21]=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN(C=O)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH2:5][C:20]1[N:21]=[C:22]([NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[N:23]=[C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:25]=1)[CH3:9]
Reactant: C=CCCC(=O)OCC
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)nc(NC(=O)C(C)(C)C)n1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1cc(NC(=O)C(C)(C)C)nc(NC(=O)C(C)(C)C)n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Ethyl 4-pentenoate (1.0 g, 7.8 mmol) was treated with 9-BBN (18.72 mL, 9.36 mmol; 0.5M in THF) at room temperature for 16 hours. To this solution was added Pd(OAc)2 (175 mg, 0.78 mmol), pyrimidine 7-2 (2.44 mg, 7.8 mmol), K2CO3 (2.15 g, 15.6 mmol), 1,1′-bis(diphenylphosphino)-ferrocene (DPPF) (433 mg, 0.78 mmol) and DMF (25 mL). The mixture was degassed with argon for 10 minutes then heated to 80° C. for 24 hours. The reaction mixture was cooled and stirred with ethanolamine (10 mL) for 3 hours. The mixture was partitioned between saturated NaHCO3 and EtOAc, washed with brine, dried (MgSO4) and concentrated. Purification by silica gel chromatography (hexane:EtOAc 2:1) afforded the title compound 7-3 as a solid.