Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][C:10](O)=[S:11])=[N:5][N:4]=[N:3]1.CN1[CH2:19][CH2:18][O:17][CH2:16]C1.ClC(OC)=O.CO[CH:27]1[CH2:32]CC[CH2:29][CH:28]1[NH2:33]>O.C(Cl)Cl>[CH3:16][O:17][CH:18]1[CH2:19][CH2:29][CH:28]([NH:33][C:10](=[S:11])[CH2:9][CH2:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[CH2:27][CH2:32]1
Reactant: COC1CCCCC1N
Reactant: CN1CCOCC1
Reactant: Cn1nnnc1CCCC(O)=S
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COC1CCC(NC(=S)CCCc2nnnn2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To methylene chloride (50 ml) are added 4-(1-methyl-1,2,3,4-tetrazol-5yl)thio-butyric acid (45 mmole) and N-methylmorpholine (50 mmole). To the mixture is added dropwise with stirring methyl chloroformate (50 mmole) with keeping the inner temperature at 10°-20° C. by ice-cooling, and thereafter, the mixture is stirred at room temperature for 30 minutes. To the mixture is added 2-methoxycyclohexylamine (54 mmole), and the mixture is stirred at the same temperature for 4 hours. After the reaction, water is added to the reaction mixture. The organic layer is separated and washed with dilute aqueous sodium hydroxide solution, diluted hydrochloric acid and water in order, and dried over sodium sulfate. Inorganic materials are filtered off, and the mother liquor is concentrated. The resulting residue is subjected to column chromatograpy (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-(4-methoxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (yield: 43%), colorless liquid, nD11 =1.5263.
Reaction SMILES: C(OC([NH:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[C:18]([OH:20])=[O:19])=O)(C)(C)C.S(Cl)([Cl:23])=O.[CH3:25]O>>[ClH:23].[NH2:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[C:18]([O:20][CH3:25])=[O:19]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC1c2ccccc2CC1C(=O)O
Product: COC(=O)C1Cc2ccccc2C1N
Product: Cl
Reaction time: 8 h

Procedure:
To a suspension of 750 mg of rac-(1R,2R)-1-[(tert-butoxycarbonyl)amino]indane-2-carboxylic acid in 15 ml of methanol was added 0.40 ml of thionyl chloride, followed by stirring overnight. The solvent was evaporated to about a half amount thereof under reduced pressure, to the obtained residue was added diethyl ether, and the insoluble material was collected by filtration and dried to obtain 512 mg of methyl rac-(1R,2R)-1-aminoindane-2-carboxylate hydrochloride.
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[K+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:30])(=O)=O)=CC=1.O>CCOCC>[C:1]1([C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[F:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(F)(C(=O)OCC)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
1 millimole of diethyl phenylmalonate was stirred with potassium hydride in 2 milliliters ether for 30 minutes at -25° C. 1.2 molar equivalents N-fluorobenzenesulfonimide prepared according to Example 1 above in 2 milliliters ether were dropped into the mixture which was stirred for 1 hour at -20° C. The mixture was allowed to warm up to room temperature and water was added. The product was extracted into ether which was dried and evaporated. Purification was carried out on a silica gel column. C6H5CF(COOCH2CH3)2 was obtained in 47% yield.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[N:12]3[CH2:13][NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1.[CH3:23][NH:24][CH3:25]>C1COCC1>[ClH:1].[CH3:23][N:24]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[N:12]3[CH2:13][NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1)[CH3:25]
Reactant: O=c1n(-c2ccc(CCl)cc2)nc2n1CNc1ccccc1-2
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(-n2nc3n(c2=O)CNc2ccccc2-3)cc1
Product: Cl
Temperature: 40 °C

Procedure:
A mixture of 2-[4-(chloromethyl)-phenyl]-5,6-dihydro-1,2,4-triazolo[4,3-c]-quinazolin-3-one (Compound 20) (150 mg, 0.48 mmol) and dimethylamine (1 ml, 40% in H2O) in THF was heated at 40° C. for 1.5 hours. The reaction was extracted with CH2Cl2 (3×50 ml) and the combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and saturated HCl/ethyl acetate solution was added to yield 2-[4-(N,N-dimethylaminomethyl)phenyl]-5,6-dihydro-1,2,4-triazolo-[4,3-c]quinazolin-3-one hydrochloride (Compound 21), m.p. 244°-247° C.
Reaction SMILES: O1CCCC1.[NH3:6].Cl[C:8]1[C:9]2[C:16]([I:17])=[CH:15][N:14]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[C:10]=2[N:11]=[CH:12][N:13]=1.C(Cl)(Cl)Cl>O>[NH2:6][C:8]1[C:9]2[C:16]([I:17])=[CH:15][N:14]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(I)c3c(Cl)ncnc32)C1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(n2cc(I)c3c(N)ncnc32)C1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Tetrahydrofuran (2.5 ml) and 28% aqueous ammonia (2.5 ml) were added to the tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate (350 mg) obtained in Step 1 above. The reaction mixture was stirred at 100° C. for 1.5 hours using a microwave reactor. Chloroform and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a white solid (340 mg). Physical properties: m/z [M+H]+ 416.0
Reaction SMILES: [CH:1]1[C:6]([C@@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.S(Cl)([Cl:15])=O.[CH3:17]O>>[CH3:17][O:9][C:8]([C@H:7]([NH2:11])[C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[CH:2][CH:1]=1)=[O:10].[ClH:15]
Reactant: CO
Reactant: N[C@@H](C(=O)O)c1ccc(O)cc1
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@H](N)c1ccc(O)cc1
Product: Cl
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
D-4-Hydroxyphenylglycine 11 (10.1 g, 60.4 mmol) was suspended in methanol (100 ml), and thionyl chloride (5.2 ml, 72.5 mmol) was added dropwise thereto at 50° C. over 0.5 hrs. After further keeping at 50° C. for 3 hrs, the solvent was distilled off under reduced pressure, and toluene and ethyl acetate were added to the residue. A resulting solid was collected by filtration and dried in vacuo to give D-4-hydroxyphenylglycine methyl ester hydrochloride 12 (12.5 g, yield 95.3%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([F:13])=[CH:5][CH:4]=1.[C-:14]#[N:15].[Na+].O>CN(C)C=O>[F:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH2:2][C:14]#[N:15])=[CH:4][CH:5]=1
Reactant: Fc1ccc(CCl)c2ccccc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(F)c2ccccc12
Temperature: 70 °C

Procedure:
A solution of 1-chloromethyl-4-fluoronaphthalene (5.45 g, 5.66 mmol), sodium cyanide (333 mg, 6.79 mmol), and water (2 mL) in N,N-dimethylformamide (30 mL) is stirred for 8 h, then heated at 70° C. for 15 h. The mixture is cooled to room temperature and partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic portion is washed with three portions of water, one portion of brine, dried (sodium sulfate), filtered and evaporated. The residue is chromatographed on SiO2 (30% ethyl acetate/hexane) to yield the title compound, 4.67 g (90%), as a light brown solid. 1H NMR (CDCl3): δ 8.19 (d, J=8 Hz, 1H), 7.87 (d, J=8 Hz, 1H), 7.68 (ddd, J=8, 7, 1 Hz, 1H), 7.63 (ddd, J=8, 7, 1 Hz, 1H), 7.51 (dd, J=8, 5 Hz, 1H), 7.14 (dd, J=10, 8 Hz, 1H), 4.09 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][N:9](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:10][C:5]2=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][NH:9][CH2:10][C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2c(n1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 2-chloro-6-trityl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine and trifluoroacetic acid. Light brown solid. MS (m/e): 154.9 ([M+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=4[Cl:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccccc1Cl
Yield: 14.7 %

Procedure:
As described in Example 9, 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.315 g (1.8 mmol) of 2-chlorobenzoyl chloride in dichloromethane. The product is chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1:1) as solvent to give a solid. Recrystallization from hexane-dichloromethane gives 100 mg of crystals, m.p. 110°-115° C. Anal. Calc'd for C28H21ClN2 O2 1/2 H2O: C,72.8; H,4.8; N,6.1; Cl,7.7. Found: C,72.6; H,4.5; N,5.8; Cl,8.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:15])=[C:10]([F:22])[CH:9]=2)[CH:7]=1.CC1C=CC(O[C@H:30]([CH3:35])[C:31]([O:33]C)=[O:32])=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][C@@H:30]([CH3:35])[C:31]([OH:33])=[O:32])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:15])=[C:10]([F:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(CC)NC(=O)c1ccc(-c2cc(Cl)ccc2O)cc1F
Reactant: COC(=O)[C@@H](C)Oc1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCC(CC)NC(=O)c1ccc(-c2cc(Cl)ccc2O[C@@H](C)C(=O)O)cc1F
Temperature: 50 °C
Reaction time: 16 h

Procedure:
The product of step c) (300 mg), the product of step d) (219 mg) and potassium carbonate (135 mg) in acetonitrile (10 ml) were charged to a flask and stirred at 50° C. for 16 h. The reaction mixture was cooled, diluted with water (20 ml) and extracted with diethyl ether (3×10 ml). The organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting yellow oil was dissolved in a 1:1 mixture of THF/methanol (10 ml) and 1M NaOH added (1.1 ml). The mixture was stirred at room temperature for 4 h and then concentrated in vacuo. The residue was purified by RPHPLC to give the title compound as a white solid (175 mg).
Reaction SMILES: C([C@H]1NC(C)(C)N(C)C1=O)C1C=CC=CC=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:27])(=O)=O)=CC=1.CC(C)=O.[Br:41][C:42]1[CH:43]=[C:44]([CH2:48][CH:49]=[O:50])[CH:45]=[CH:46][CH:47]=1>CCOCC.C(O)(C)C>[F:27][C@H:48]([C:44]1[CH:45]=[CH:46][CH:47]=[C:42]([Br:41])[CH:43]=1)[CH:49]=[O:50]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: O=CCc1cccc(Br)c1
Agent: CN1C(=O)[C@@H](Cc2ccccc2)NC1(C)C
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C[C@H](F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A homogeneous mixture of (5R)-5-benzyl-2,2,3-trimethyl imidazolidin-4-one dichloroaccetic acid salt (97 mg, 0.4 mmol) and N-fluorobenzenesulfonimide (3.15 g, 10 mmol) in a 9:1 mixture of acetone and isopropanol at room temperature is treated with (3-bromophenyl)acetaldehyde (280 mg, 1.4 mmol), stirred for 1 h at room temperature, cooled to −78° C., diluted with ether, and filtered through a pad of celite. The filtercake is washed with additional ether. The combined filtrates are treated with methylsulfide (5 mL), washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure to give (R)-2-fluro-2-(3-bromophenyl)acetaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]#[CH:16])=[CH:9][C:8]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=1)=O.[O-:31][C:32]#[N:33].[Na+]>CC(O)=O.O>[OH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:7]2[C:8](=[CH:9][C:10]([O:13][CH2:14][C:15]#[CH:16])=[CH:11][CH:12]=2)[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[N:33][C:32]1=[O:31]
Reactant: N#C[O-]
Reactant: C#CCOc1ccc(NCc2cccc(O)c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.0 g (7.51 mmol) of the product prepared in step A in 45 ml AcOH is treated with 732 mg (11.3 mmol) sodium cyanate. The dark red solution is stirred for 2 h at rt. The resulting yellow-orange suspension is diluted with water and filtered. The orange product is washed well with water and diethyl ether to yield an orange solid. m.p. 230° C.
Reaction SMILES: [F:1][C:2]1[CH:52]=[CH:51][C:5]([C:6]([N:8]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:49]=[CH:48][C:25]4[N:26]([C:29]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:27]=[N:28][C:24]=4[CH:23]=3)[CH:19]=[CH:18][C:17]=2[F:50])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[CH:53](I)([CH3:55])[CH3:54].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:49]=[CH:48][C:25]4[N:26]([C:29]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:27]=[N:28][C:24]=4[CH:23]=3)[CH:19]=[CH:18][C:17]=2[F:50])[CH:9]2[CH2:14][CH2:13][N:12]([CH:53]([CH3:55])[CH3:54])[CH2:11][CH2:10]2)=[O:7])=[CH:51][CH:52]=1
Reactant: O=C(c1ccc(F)cc1)N(Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F)C1CCNCC1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1CCC(N(Cc2cc(-c3ccc4c(c3)nnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)ccc2F)C(=O)c2ccc(F)cc2)CC1
Reaction time: 240 h
Yield: 61.5 %

Procedure:
A mixture of 4-Fluoro-N-[2-fluoro-5-(1-trityl-1H-benzotriazol-5-yl)-benzyl]-N-piperidin-4-yl-benzamide (25 mg, 0.04 mmol), isopropyl iodide (34 mg, 0.2 mmol) and potassium carbonate (28 mg, 0.2 mmol) in 2 mL of DMF was heated at 40° C. for 3 h when additional isopropyl iodide (34 mg, 0.2 mmol) was added. The mixture was heated for an additional 2 h and then left at ambient temperature for 10 days. The mixture was diluted with water and the product extracted into ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 18 mg of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[NH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([NH:20][C:14]([C:12]2[CH:11]=[N:10][C:9]([CH:17]3[CH2:19][CH2:18]3)=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1cnc(C2CC2)c(-c2cccc(Cl)c2)n1
Product: O=C(NN1CCCCC1)c1cnc(C2CC2)c(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid (Example 3a) and 1-amino-piperidine as starting materials, and isolated (29 mg, 40%) as white solid; LC-MS (UV peak area, ESI) 100%, 357.1485 (M+H).
Reaction SMILES: [C:1]([Si:5]([CH3:36])([CH3:35])[O:6][CH:7]([CH2:11][CH2:12][CH:13]1[CH:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:21]2[C:16](=[C:17]([F:34])[CH:18]=[CH:19][C:20]=2[F:33])[O:15][CH2:14]1)[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CS(Cl)(=O)=O.CC([O-])(C)C.[K+]>C(Cl)Cl.C1COCC1>[C:1]([Si:5]([O:6][CH:7]1[CH2:11][CH2:12][CH:13]2[CH2:14][O:15][C:16]3[C:21]([C:22]2([S:23]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH2:9][CH2:8]1)=[C:20]([F:33])[CH:19]=[CH:18][C:17]=3[F:34])([CH3:36])[CH3:35])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC(CCO)CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC2COc3c(F)ccc(F)c3C2(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A solution of 3-(tert-butyl-dimethyl-silanyloxy)-5-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-pentan-1-ol (730 mg, 1.30 mmol) in CH2Cl2 (10 mL) at 0° C. was treated with Et3N (360 μL, 2.6 mmol) followed by MsCl (150 μL, 1.95 mmol). After 30 min, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with CH2Cl2 (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo to provide the crude product. The residue was dissolved in THF (13 mL), cooled to 0° C. and treated with KOt-Bu (1 M in THF, 3.0 mL, 3.0 mmol). After 1 h, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over MgSO4 and concentrated in vacuo to give the title compound (700 mg, 99% over 2 steps): 1H NMR (CDCl3 400 MHz) δ 7.63 (dd, J=8.8, 1.5 Hz, 2H), 7.49 (dd, J=8.8, 1.5 Hz, 2H), 7.04 (m, 1H), 6.43 (m, 1H), 5.07 (dd, J=10.9, 2.2 Hz, 1H), 4.23 (m, 1H), 4.04 (m, 0.5H), 3.58 (m, 0.5H), 2.97 (m, 1H), 2.71-2.26 (m, 2H), 2.10 (m, 1H), 1.83-1.43 (m, 5H), 0.90 (s, 4.5H), 0.77 (s, 4.5H), 0.03 (s, 3H), −0.01 (s, 3H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:12]=[C:11]([NH2:13])[S:10][N:9]=1)[C:5]([OH:7])=O.P(Cl)(Cl)(Cl)=O.[NH2:19][CH:20]1[C:35](=[O:36])[N:22]2[C:23]([C:32]([OH:34])=[O:33])=[C:24]([CH2:27][O:28][C:29](=[O:31])[NH2:30])[CH2:25][S:26][C@H:21]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:12]=[C:11]([NH2:13])[S:10][N:9]=1)[C:5]([NH:19][CH:20]1[C:35](=[O:36])[N:22]2[C:23]([C:32]([OH:34])=[O:33])=[C:24]([CH2:27][O:28][C:29](=[O:31])[NH2:30])[CH2:25][S:26][C@H:21]12)=[O:7]
Reactant: CON=C(C(=O)O)c1nsc(N)n1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
A mixture of 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer)(1.01 g) and phosphorus oxychloride (3.06 g) in methylene chloride (25 ml) was stirred for 2 hours at ambient temperature, cooled to 0° C. and thereto was added N,N-dimethylformamide (2.0 ml), followed by stirring for an additional 45 minutes at 0° C. A mixture of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (4.9 g) and trimethylsilylacetamide (11 g) in methylene chloride (100 ml) was warmed to make a clear solution. The solution was cooled to -15° C. and added to the above obtained solution, followed by stirring for 30 minutes at 0° C. The reaction mixture was poured into a cold aqueous solution of sodium bicarbonate. The aqueous layer was separated and thereto was added ethyl acetate. The resulting mixture was adjusted to pH 2 with 10% hydrochloric acid, filtered to remove an insoluble material and then saturated with sodium chloride. The ethyl acetate layer was separated, dried over magnesium sulfate and evaporated. The residue was triturated with diethyl ether to give a crude product of the title compound (1.2 g). The crude material was dissolved in an aqueous solution of sodium bicarbonate, and reprecipitated with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give the title compound (0.35 g), mp. 185° to 190° C. (dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][CH:10]=[N:9][CH:8]=1.[CH2:12]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](O)=[O:28])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:28]=[C:27]([C:10]1[O:11][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][N:9]=1)[CH2:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:20][CH:21]=1
Reactant: O=C(O)CCc1ccc(Cc2ccccc2)cc1
Reactant: c1ccc(-c2cnco2)nc1
Product: O=C(CCc1ccc(Cc2ccccc2)cc1)c1ncc(-c2ccccn2)o1
Yield: 59 %

Procedure:
This material was prepared from 5-(2-pyridyl)oxazole and 3-(4-benzylphenyl)propanoic acid (S40) using General Procedure B. PTLC (SiO2, 50% EtOAc-hexanes) afforded 11h (95 mg, 0.59 mmol, 59%) as a light tan oil: 1H NMR (CDCl3, 500 MHz) 8.68 (app d, 1H, J=4.8 Hz), 7.88 (s, 1H), 7.84 (d, 1H, J=7.7 Hz), 7.81 (td, 1H, J=7.7, 1.8 Hz), 7.33-7.27 (m, 3H), 7.21-7.12 (m, 7H), 3.96 (s, 2H), 3.45 (t, 2H, J=7.7 Hz), 3.09 (t, 2H, J=7.7 Hz); 13C NMR (CDCl3, 125 MHz) 187.3, 157.1, 153.2, 150.0, 146.1, 141.1, 139.0, 138.0, 137.0, 129.0, 128.8, 128.5, 128.3, 126.9, 125.9, 124.1, 120.3, 41.4, 40.6, 29.2; IR (film) νmax 3025, 2920, 1694, 1601, 1574, 1516, 1494, 1468, 1426, 1381, 1283, 1151, 1118, 1064, 990, 963, 936, 913, 849, 784, 727, 696 cm−1; ESI-TOF m/z 369.1600 (C24H20N2O2+H+ requires 369.1597).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[C:6]([NH:10][C:11]([NH2:13])=[O:12])[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH2:8][Cl:16])=[C:6]([NH:10][C:11]([NH2:13])=[O:12])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(NC(N)=O)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc(NC(N)=O)c1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A mixture of 6-methyl-2-ureidobenzyl alcohol (1 g) and thionyl chloride (0.66 g) in methylene chloride (20 ml) was stirred for 2 hours at room temperature and evaporated in vacuo. The residue was washed with water and dried in a desiccator to give 6-methyl-2-ureidobenzyl chloride (0.66 g).