Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=O)[C@H:10]2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[S:33])[C@H:10]2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@H]2F)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)[C@H]2F)CC1
Temperature: 60 °C
Yield: 150.1 %

Procedure:
4-(S)-(1-Ethoxycarbonylcyclopropyl)-3-(S)-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidone (6.86 g, 21.48 mmol) was dissolved in dry toluene (100 ml), and the solution was mixed with Lawesson's reagent (5.21 g, 12.89 mmol) and heated at 60° C. for 30 minutes. After cooling, toluene was evaporated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=4:1, to thereby obtain 6.49 g (90.1%) of the title compound as a light yellow oil.
Reaction SMILES: C(O)C.[OH-].[Na+].[CH3:6][S:7][C:8]([CH3:25])([CH3:24])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:23])[CH2:13][CH:14]=[CH:15][C:16]([CH3:22])=[CH:17][C:18]([O:20]C)=[O:19]>O>[CH3:6][S:7][C:8]([CH3:24])([CH3:25])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:23])[CH2:13][CH:14]=[CH:15][C:16]([CH3:22])=[CH:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)C=C(C)C=CCC(C)CCCC(C)(C)SC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSC(C)(C)CCCC(C)CC=CC(C)=CC(=O)O

Procedure:
To 350 ml. of ethanol, 105 ml. of water and 70 ml. of 50% aqueous sodium hydroxide is added 46.5 g. of methyl 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoate. The mixture is refluxed for about 18 hours. After cooling, alcohol is removed in vacuo. Water is added followed by acidification and then extraction with ether to yield 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoic acid.
Reaction SMILES: [CH3:1]I.[Mg].[Cl-].[C:5]1([CH2:11][N+:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>CCOCC>[C:5]1([CH2:11][N:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]2[CH3:1])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc[n+](Cc2ccccc2)cc1C
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1=C(C)C(C)N(Cc2ccccc2)C=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A solution of methyl iodide (112 mL, 1.8 mole) in ether (225 mL) was added dropwise to a suspension of magnesium turnings (44 g, 1.8 mole) in ether (225 ml) under nitrogen over a period of 1 hour. The mixture was stirred at room temperature for 1 hour, transferred into a 1000 mL addition funnel and then was added to a suspension of N-(phenylmethyl)-3,4-dimethylpyridinium chloride (350.7 g, 1.5 mole) in ether (1500 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours and was then poured into a solution of saturated ammonium chloride (3 L). The organic layer was separated and the aqueous layer was extracted with ether (1000 mL). The combined ether layers were washed with water (500 mL), then brine (500 mL) and were dried over sodium sulfate and potassium carbonate-. The solvent was removed in vacuo to afford 284.1 g (76%) of 1,2-dihydro-N-(phenylmethyl)-2,3,4-trimethylpyridine, as an amber oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[C@@H:26]([C:33]1[CH:41]=[C:40]2[C:36]([CH:37]=[N:38][N:39]2[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:35][CH:34]=1)[CH2:27]OS(C)(=O)=O)(=O)=O>C1COCC1>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[C@:12]2([CH2:27][C@H:26]2[C:33]2[CH:41]=[C:40]3[C:36]([CH:37]=[N:38][N:39]3[CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:35][CH:34]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc2c(c1)CC(=O)N2Cc1ccccc1
Reactant: CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)c1ccc2cnn(Cc3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3cnn(Cc4ccccc4)c3c1)C(=O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 32.7 %

Procedure:
To a 250 mL round bottom flask charged with 60% NaH (1.20 g, 30 mmol) was added anhydr. THF (20 mL) and the resulting mixture was cooled to 0° C. A solution of 1-benzyl-5-methylindolin-2-one (2.37 g, 10 mmol) in dry THF (25 mL) was added over 2 min, followed by rinsing with THF (5 mL). After stirring for 20 min at 0° C., a solution of (S)-1-(1-benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate (4.24 g, 10 mmol) in dry THF (45 mL) was added dropwise through dropping funnel over 40 min, followed by rinsing with THF (5 mL). After addition, the resulting mixture was stirred for 30 min at 0° C. (TLC showed completion) then left O/N at rt. After cooling to 0° C., the reaction mixture was poured into an Erlenmeyer flask containing ice (100 mL) and sat. NH4Cl (30 mL) and extracted with EtOAc (150 mL×2), dried (Na2SO4). After removal of solvents, the residue was transferred to a 100 mL RBF using 30 mL of EtOAc and cyrstals formed. Suction filtration gave the title compound as a beige solid (1.537 g). The filtrate was concentrated and purified by Biotage Isolera (20-30% EtOAc in hexane) and triturated with EtOAc/hexane to give 2nd crop as off white solid (1.560 g). The filtrate was purified using the above procedure to give 3rd crop as a beige solid (115 mg). Total 3.212 g (68%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.36-7.20 (m, 9H), 7.14 (d, J=6.0 Hz, 2H), 6.94 (d, J=8.4 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.64 (d, J=7.2 Hz, 1H), 5.62 (d, J=16.8 Hz, 1H, partially overlapping with s at 5.59), 5.59 (s, 1H, partially overlapping with d at 5.62), 5.55 (d, J=16.8 Hz, 1H), 5.08 (d, J=16.0 Hz, 1H), 4.97 (d, J=15.6 Hz, 1H), 3.48 (t, J=8.4 Hz, 1H), 2.30-2.25 (m, 1H), 2.02-1.96 (m, 1H), 1.85 (s, 3H); MS ESI 470.3 [M+H]+, calcd for [C32H27N3O+H]+ 470.2.
Reaction SMILES: CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32]CCO)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[C:36]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:37]=1.[CH2:55]1[O:59][C:58]2[CH:60]=[C:61]([OH:64])[CH:62]=[CH:63][C:57]=2[O:56]1>C1COCC1>[O:56]1[C:57]2[CH:63]=[CH:62][C:61]([O:64][CH2:36][CH2:37][N:28]3[CH:29]=[CH:30][N:31]=[C:26]([N:23]4[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]4)[C:27]3=[O:32])=[CH:60][C:58]=2[O:59][CH2:55]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: Oc1ccc2c(c1)OCO2
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: C1CCOC1
Product: O=c1c(N2CCNCC2)nccn1CCOc1ccc2c(c1)OCO2
Reaction time: 2 h
Yield: 22.7 %

Procedure:
TMAD (0.207 g, 1.20 mmol) was added to a solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-pyrazinyloxy]ethanol (0.324 g, 1.00 mmol), triphenylphosphine (0.315 g, 1.20 mmol) and sesamol (0.173 g, 1.25 mmol) in THF (1 mL) at room temperature. After being stirred for 2 h, the reaction mixture was concentrated and put through a silica column using toluene/EtOAc (7:3) as eluent. Solvents were removed in vacuo and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/H2O (50:45:5; 5 mL) for 15 min with stirring. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (20:3:3:2) as eluent. The product-containing fractions were concentrated, washed between dichloromethane/5% aqueous NaOH, and put through a silica column using dichloromethane/MeOH (8:2) to give 78 mg (23%) of the title compound. HRMS m/z calcd for C17H20N4O4 (M)+ 344.1485, found 344.1474.
Reaction SMILES: [H-].[Na+].C(OP([CH:11]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]=O>O1CCCC1>[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1/[CH:30]=[C:11](\[CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=Cc1ccco1
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1ccco1)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% oil-based sodium hydride (6.50 g) in tetrahydrofuran (400 mL) was added dropwise a solution of 4-tert-butyl 1-ethyl 2-(diethoxyphosphoryl)succinate (55.0 g) in tetrahydrofuran (100 mL) under ice-cooling over 30 minutes, and then the mixture was stirred under the cooling for 1 hour. Then, thereto was added a solution of 2-furaldehyde (12.8 mL) in tetrahydrofuran (40 mL) under ice-cooling over 15 minutes, and the mixture was stirred at room temperature for 1 hour. Ice water was poured into the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure to give 4-tert-butyl 1-ethyl (2E)-2-(2-furylmethylene)succinate (47.0 g) as a brown oil crude. Then, the oil (47.0 g) was stirred in trifluoroacetic acid (100 mL) at room temperature for 1 hour, and then concentrated under reduced pressure. The resulting residue was treated azeotropically with toluene several times to give (3E)-3-(ethoxycarbonyl)-4-(2-furyl)-but-3-enoic acid (39.2 g) as a brown oil crude. Then, the oil (39.2 g) was dissolved in acetic anhydride (100 mL), and thereto was added potassium acetate (19.8 g), and then the mixture was heated to reflux for 45 minutes. The reaction mixture was let stand to be cooled, and then thereto was added water (100 mL), and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to give ethyl 4-(acetyloxy)benzofuran-6-carboxylate (24.7 g) as a pale orange solid. APCI-MS m/z: 266 [M+NH4]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([F:38])=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH:22]=1.Cl.CC(O)C>CN(C=O)C>[F:38][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C:2]3[CH:3]=[C:4]4[C:17](=[CH:18][CH:19]=3)[CH2:16][C@@:6]3([C:14]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:7]3=[O:15])[CH2:5]4)[CH:22]=1)=[O:28])[CH2:30][CH2:31]2
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Reactant: Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: O=C(c1cc(Nc2ccc3c(c2)C[C@]2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cc(F)ccc21

Procedure:
0.10 g (0.40 mmol) (S)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 0.11 g (0.40 mmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 13 μL of a 4 molar aqueous hydrochloric acid solution were added to 2.0 mL of 2-propanol and the mixture was refluxed for 4 h. Then the reaction mixture was dissolved in DMF and purified by preparative HPLC-MS. The product-containing fractions were combined and the organic solvent was evaporated down. The residue was made alkaline with a 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [F:1][C:2]1[C:9](F)=[C:8]([F:11])[C:7]([F:12])=[C:4]([C:5]#[N:6])[C:3]=1[C:13]#[N:14].[OH:15][C:16]([C@H:19]1[CH2:23][CH2:22][NH:21][C@H:20]1[CH3:24])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Li+].[Li+]>>[F:12][C:7]1[C:8]([F:11])=[C:9]([N:21]2[CH2:22][CH2:23][C@H:19]([C:16]([OH:15])([CH3:18])[CH3:17])[C@@H:20]2[CH3:24])[C:2]([F:1])=[C:3]([C:13]#[N:14])[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1C#N
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1c(F)c(F)c(C#N)c(C#N)c1F

Procedure:
Using 3,4,5,6-tetrafluorophthalonitrile (464 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (480 mg) and lithium carbonate (362 mg), the title compound was obtained as a pale-yellow solid (yield: 250 mg) by an operation similar to that in Example 3.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:23])[C@H:17]2[C@@H:13]1[C@H:14]([C:19]([Cl:22])([Cl:21])[Cl:20])[O:15][C:16]2=[O:18].Cl>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH3:23])[C@H:17]2[C@@H:13]1[C@H:14]([C:19]([Cl:22])([Cl:20])[Cl:21])[O:15][C@@H:16]2[OH:18]
Reactant: CC1(C)[C@H]2[C@H](C(Cl)(Cl)Cl)OC(=O)[C@H]21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H]2[C@H]1[C@@H](O)O[C@H]2C(Cl)(Cl)Cl
Temperature: -60 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
75 ml of a toluene solution of 20% of diisobutylaluminum hydride were slowly added at -60° C. to a solution of 20 g of (1R,4R,5S) 6,6-dimethyl-4-trichloromethyl-3-oxa-bicyclo(3,1,0)-hexane-2-one in 200 ml of toluene and the mixture was stirred at -60° C. for one hour and was poured into an ice-water mixture. Aqueous N hydrochloric acid was added to the mixture to adjust the pH to 3 to 4 and the mixture was filtered. The decanted benzene phase was washed with aqueous sodium bicarbonate solution, with water and evaporated to dryness under reduced pressure. The residue was added to petroleum ether (b.p.=35°-70° C.) and the mixture was filtered to obtain 14.5 g of (1R,2S,4R,5S) 6,6-dimethyl-4-trichloromethyl-3-oxa-bicyclo(3,1,0)hexan-2-ol melting at 140° C.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[NH:11][C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[H-].[Na+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][CH2:39]Br)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O>[CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[N:9]([CH2:39][CH2:38][CH2:37][CH:34]3[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[CH2:32][CH2:33]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCBr)CC1
Reactant: C=CCc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 100 ml round bottom flask, under a nitrogen atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]benzimidazole (550 mg, 1.84 mmol) and anhydrous N,N-dimethylformamide (59 ml). To this solution was added sodium hydride (60% in mineral oil, 81.04 mg, 2.03 mmol). The resulting mixture was stirred at room temperature for 60 minutes, and then 3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl bromide (620 mg, 2.03 mmol) was added. The resulting mixture was heated to 100° C. and stirred at this temperature for about three hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between ethyl acetate and brine. The aqueous fraction was extracted twice with brine. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
Reaction SMILES: C(O[C:4](=[O:21])[CH2:5][O:6][C:7]1[C:8](Cl)=[N:9][C:10]([Cl:19])=[N:11][C:12]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)C.CN.[CH2:24]([N:26](CC)CC)C>>[Cl:19][C:10]1[N:11]=[C:12]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:7]2[O:6][CH2:5][C:4](=[O:21])[N:26]([CH3:24])[C:8]=2[N:9]=1
Reactant: CCOC(=O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Reactant: CCN(CC)CC
Agent: CN
Product: CN1C(=O)COc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 140 °C
Yield: 37.5 %

Procedure:
A mixture of (2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-acetic acid ethyl ester (501 mg, 1.49 mmol), methylamine (1.0 mL, 2.0 mmol, 2 M in THF) and triethylamine (250 μL, 1.79 mmol) in IMS (10 mL) was heated at 140° C. for 35 minutes using microwave irradiation. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (SiO2, 0-20% ethyl acetate in cyclohexane) affording 2-Chloro-8-methyl-4-morpholin-4-yl-8H-pyrimido[5,4-b][1,4]oxazin-7-one (159 mg, 38%). LCMS: RT=2.93 min, [M+H]+=285/287.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][C:15]([O:20][CH3:21])([O:18][CH3:19])[CH2:16]Br.O>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:16][C:15]([O:20][CH3:21])([O:18][CH3:19])[CH2:14]2)=[CH:6][CH:5]=1
Reactant: COC(CBr)(CBr)OC
Reactant: N#CCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(OC)CC(C#N)(c2ccc(Br)cc2)C1
Temperature: 60 °C
Reaction time: 20 h
Yield: 57.4 %

Procedure:
A suspension of sodium hydride (2 g, 50.0 mmol) in DMF (20 ml) was cooled to 0 degree before 2-(4-bromophenyl)acetonitrile (4 g, 20.40 mmol) was added slowly, The suspension was stirred at 0 degree for another 10 min before 1,3-dibromo-2,2-dimethoxypropane (2.62 g, 10.00 mmol) was added. The reaction mixture was stirred at 60° C. for 20 h before cooled to room temperature, poured into water (75 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phase was washed with water (75 ml), brine (50 ml) and concentrated. The crude product was purified by column (100 g, biotage) eluted with ethyl acetate/cyclohexane (0-10%) to afford product 1.7 g (59% yield). 1H NMR (500 MHz, DMSO-d6): 7.46 (d, 2H), 7.29 (d, 2H), 3.21 (s, 3H), 3.11 (s, 3H), 3.03 (d, 2H), 2.62 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]([CH3:7])[N:4]([CH2:8][C:9]([OH:11])=O)[N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[CH:20]1[O:24][N:23]=[C:22]([C:25]2[N:26]=[C:27]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH2:21]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[CH:20]1[O:24][N:23]=[C:22]([C:25]2[N:26]=[C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:9](=[O:11])[CH2:8][N:4]4[CH:5]([CH3:7])[CH2:6][C:2]([CH3:1])=[N:3]4)[CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH2:21]1
Reactant: CC1=NN(CC(=O)O)C(C)C1
Reactant: Fc1cccc(F)c1C1CC(c2csc(C3CCNCC3)n2)=NO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=NN(CC(=O)N2CCC(c3nc(C4=NOC(c5c(F)cccc5F)C4)cs3)CC2)C(C)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4,5-dihydro-3,5-dimethyl-1H-pyrazole-1-acetic acid (i.e. the product of Step B) (0.10 g, 0.64 mmol), 4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]piperidine (i.e. the product of Example 1, Step D) (175 mg, 0.5 mmol), N3-(ethylcarbodimidoyl)-N1,N1-dimethyl-1,3-propanediamine hydrochloride (191 mg, 1.0 mmol), 1-hydroxybenzotriazole (5 mg, 0.037 mmol) and triethylamine (0.14 mL, 1.0 mmol) in dichloromethane (4 mL) was stirred at room temperature. After 6 h, more N3-(ethylcarbodimidoyl)-N1,N1-dimethyl-1,3-propanediamine hydrochloride (191 mg, 1.0 mmol) and triethylamine (0.14 mL, 1.0 mmol) were added to the reaction mixture. After 3 days, the reaction mixture was diluted with dichloromethane, washed with saturated aqueous ammonium chloride solution and concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography on silica gel (0 to 100% gradient of ethyl acetate in hexanes, and then 20% methanol in ethyl acetate as eluant) to provide the title compound, a compound of the present invention, as a tan solid (124 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([NH2:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[C:29]([NH:48][C:49]1[S:50][CH:51]=[C:52](/[C:54](=[N:67]/[O:68][CH2:69][CH2:70][CH2:71][CH3:72])/[C:55](ON2C3C=CC=CC=3N=N2)=[O:56])[N:53]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O.C(NC1SC=C(/C(=N/OC)/C(N[C@@H]2C(=O)N3C(C(O)=O)=C(CSC4N(NC(=O)C)N=NN=4)CS[C@H]23)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC(N(C)C)=O>[C:29]([NH:48][C:49]1[S:50][CH:51]=[C:52](/[C:54](=[N:67]/[O:68][CH2:69][CH2:70][CH2:71][CH3:72])/[C:55]([NH:1][C@@H:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]4[N:15]([NH2:16])[N:14]=[N:13][N:12]=4)[CH2:7][S:8][C@H:3]23)=[O:56])[N:53]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCCO/N=C(\C(=O)On1nnc2ccccc21)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Agent: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCCCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 33.6 %

Procedure:
A solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (0.653 g, 2 mmol), triethylamine (0.405 mg, 4 mmol) and 1-benzotriazolyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-n-butoxyiminoacetate (1.32 g, 2.2 mmol) in dimethylacetamide (6 ml) and water (0.6 mol) was treated in a manner similar to that described in Example 6, (c) to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-n-butoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (0.535 g, 33.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]([CH3:32])[S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](Br)[CH:25]=1)(=[O:23])=[O:22]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:26]1[CH:25]=[C:24]([S:21]([N:20]([CH3:32])[CH3:19])(=[O:22])=[O:23])[CH:29]=[CH:28][C:27]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N(C)C)cc1Br
Product: Cc1ccc(S(=O)(=O)N(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and N,N-dimethyl 3-bromo-4-methylbenzenesulfonamide (Combiblocks), the title compound was obtained as an orange sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH3:15])=O)(C)(C)C.C([Li])(C)(C)C.CON(C)C(=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C:6]2[NH:8][C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[CH:15]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: Cc1cnccc1NC(=O)OC(C)(C)C
Agent: [Li]C(C)(C)C
Product: c1ccc(-c2cc3cnccc3[nH]2)cc1

Procedure:
4-tert-Butoxycarbonylamino-3-methylpyridine (Example 11a, 1.0 g, 4.8 mmol) was dilithiated with t-butyllithium and treated with N-methoxy-N-methylbenzamide (0.95 g, 5.76 mmol) as described previously. The crude product was purified by trituration with ethyl acetate to afford the title compound as a pale beige solid; yield: 0.59 g (63%); mp 276°-278°C.[Lit. mp 282°-283° C.].