Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:48]([O:52][C:53]([NH:55][C@@H:56]1[CH2:61][C@H:60]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:59][N:58]([C:70]2[CH:75]=[C:74]([N:76]3[CH2:81][C@@H:80]([NH:82][C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[CH2:79][C@@H:78]([NH:90][C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:77]3)[N:73]=[C:72]([NH:98][C:99]3[CH:104]=[CH:103][C:102]([NH2:105])=[CH:101][CH:100]=3)[CH:71]=2)[CH2:57]1)=[O:54])([CH3:51])([CH3:50])[CH3:49]>CC(N(C)C)=O.CCOC(C)=O>[C:48]([O:52][C:53]([NH:55][C@@H:56]1[CH2:61][C@H:60]([NH:62][C:63]([O:65][C:66]([CH3:67])([CH3:68])[CH3:69])=[O:64])[CH2:59][N:58]([C:70]2[CH:75]=[C:74]([N:76]3[CH2:77][C@@H:78]([NH:90][C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:79][C@@H:80]([NH:82][C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[CH2:81]3)[N:73]=[C:72]([NH:98][C:99]3[CH:104]=[CH:103][C:102]([NH:105][C:12]([C:3]4[CH:4]=[CH:5][C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]=4[OH:1])=[O:14])=[CH:101][CH:100]=3)[CH:71]=2)[CH2:57]1)=[O:54])([CH3:49])([CH3:50])[CH3:51]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2cc(Nc3ccc(N)cc3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2cc(Nc3ccc(NC(=O)c4ccc5ccccc5c4O)cc3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
1-Hydroxy-naphthalene-2-carboxylic acid (142) (0.018 g, 0.096 mmol) was dissolved in DMA (2 mL), iPr2EtN (0.096 mmol) was added followed by HBTU (0.036 g, 0.096 mmol) and the mixture was shaken in an 8 mL Teflon septum capped vial at room temperature for 20 minutes. 4,6-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-2-(4-aminophenyl-amino)-pyridine (168) (0.055 g, 0.0677 mmol) was added and the mixture was shaken at room temperature for 16 h. LC-MS indicated complete coupling at this point. The mixture was diluted with EtOAc (25 mL) and the organic layer washed with water (15 mL), NaHCO3 (aqueous sat., 15 mL) and brine (15 mL) via extraction, dried over MgSO4 and concentrated to give a brown oil. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (eluding with 15–100% EtOAc in hexane for 30 min) gave the desired product (170) as an off-white powder upon concentration (0.042 g, 0.043 mmol, 64% yield). LC-MS (ESI): (exact mass: 981.53) m/e=982.6 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:26])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:27]([O:29]C)=[O:28])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:31]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:26])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:27]([OH:29])=[O:28])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:31]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N3CCCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of (S)-methyl 2-(5-fluorobenzofuran-2-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate (120 mg, 0.29 mmol) in MeOH (20 mL) was added sodium hydroxide (46 mg, 1.15 mmol) and water (3 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (10 mL) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)-2-(5-fluorobenzofuran-2-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (113 mg, 97%).
Reaction SMILES: [CH3:1][N:2]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[C:13]=1[C:21](OCC)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-])=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>[Ti](Cl)(Cl)(Cl)Cl.C1(OC)C=CC=CC=1>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[C:21]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)[C:13]2[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[S:16][C:12]1=2
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(N(C)c2ccccc2[N+](=O)[O-])sc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3ccccc3N(C)c3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(N-methyl-2-nitroanilino)benzo[b]thiophene-3-carboxylate (3.2 g), 1-methylpiperazine, anisole (80 ml) and titanium tetrachloride (3.5 ml), 6-methyl-12-(4-methylpiperazin-1-yl)[1]benzothieno[2,3-b][1,5]benzodiazepine (166 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[C:14]([CH3:21])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:22][O-:23].[Na+]>CC(N(C)C)=O>[CH3:22][O:23][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[C:14]([CH3:21])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: C[O-]
Reactant: Cc1cc(-c2cc3ncccc3c(Cl)n2)ccc1N(C)C
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1nc(-c2ccc(N(C)C)c(C)c2)cc2ncccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
100 mg (0.31 mmol) of 6.1 was placed in 0.5 ml dimethylacetamide and then 60 mg (1.1 mmol) sodium methoxide were added. The reaction mixture was stirred for 1 h at 50° C. The mixture was purified by chromatography (RP-HPLC-MS), the corresponding fractions were freeze-dried.
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[H-].[Na+].[NH2:19][C:20]1[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Cl:26])[N:25]=1>CN(C)C=O>[Cl:26][C:24]1[N:25]=[C:20]([NH:19][C:1](=[O:16])[O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: Cn1cc(Cl)nc(N)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Cl)nc(NC(=O)Oc2ccccc2)c1=O
Reaction time: 0.75 h
Yield: 57.9 %

Procedure:
A solution of 9.4 g of diphenyl carbonate and 65 ml of dimethylformamide is allowed to run into a mixture of 1.9 g of a 55% sodium hydride dispersion and 20 ml of dimethylformamide at 10°-15° C. 6.4 g of 3-amino-5-chloro-1-methylpyrazin-2-one are then introduced in portions at the same temperature and the mixture is stirred for a further 45 minutes. The mixture is filtered, the filtrate is poured into a mixture of 270 ml of ethyl aceate, 270 ml of ice-water and 42 ml of 7% hydrochloric acid, the organic phase is washed with water and sodium chloride solution and dried over sodium sulfate, the solution is concentrated and the product which has precipitated out is filtered off to give 6.5 g of phenyl N-(5-chloro-1-methylpyrazin-2-on-3-yl)-carbamate.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[O:14][C:15](=[O:29])[CH:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C:18](=O)[CH2:17]4)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].Cl.[OH:31][NH2:32].C(N(CC)CC)C.[Cl-].[NH4+]>C(O)C>[OH:31][N:32]=[C:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[CH:16]([C:15](=[O:29])[O:14][C:13]3[C@H:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:10][CH2:11]4)[CH2:17]1
Reactant: NO
Reactant: CC(C)CCC[C@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)CC1C(=O)O3
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)CCC[C@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=NO)CC1C(=O)O3
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
Compound 1 (172 mg, 0.429 mmol) obtained in Example 1 was dissolved in ethanol (4.0 mL), and hydroxyamine hydrochloride (89.5 mg, 1.29 mmol) and triethylamine (178 μL, 1.29 mmol) were added thereto at room temperature, followed by stirring for 20 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography to obtain the title compound (160 mg, 90%) as a mixture of E-form and Z-form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([CH2:16][CH2:17][CH2:18][OH:19])[C:14]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1)=[O:10].[CH3:29][Mg]Br.C(OCC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([CH2:16][CH2:17][CH2:18][OH:19])[C:14]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1)([OH:10])[CH3:29]
Reactant: CCN(CC)c1cccc2nc(C(=O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN(CC)c1cccc2nc(C(C)(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 67 %

Procedure:
To a stirred solution of (2,4-dichlorophenyl)[7-(diethylamino)-1-(3-hydroxypropyl)-1H-benzimidazol-2-yl]methanone (300 mg, 0.714 mmol) in tetrahydrofuran (7 mL) was added a solution of methyl magnesium bromide in diethyl ether (3.0 M, 714 μL, 2.14 mmol) at 0° C. After being stirred for 6.5 h at room temperature, the reaction mixture was quenched with aqueous ammonium chloride at 0° C., diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The resulting solid was washed with diethyl ether to afford the desired product as a yellow solid (210 mg, 0.481 mmol, 67%).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8](=[O:16])[C:7]2[N:17]([CH3:20])[N:18]=[CH:19][C:6]1=2.[CH2:21]([N:24]1C2C=CC(C)=CC=2C(=O)C2N(C)N=C[C:25]1=2)[CH:22]=C.C(NC)C.CO.[Cl:46]CCl>>[ClH:46].[CH2:21]([N:24]([CH3:25])[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8](=[O:16])[C:7]2[N:17]([CH3:20])[N:18]=[CH:19][C:6]1=2)[CH3:22]
Reactant: ClCCl
Reactant: C=CCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Reactant: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CCCI
Agent: CCNC
Solvent: CO
Product: CCN(C)CCCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Product: Cl

Procedure:
The title compound was prepared according to the procedure of step 2 in EXAMPLE 57 using an inseparable mixture of 4-(3-iodopropyl)-1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one and 4-allyl-1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 59, step 1) and N-ethylmethylamine instead of dimethylamine. The title compound and 4-allyl-1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one were separable by column chromatography on silica gel eluting with methanol/dichloromethane (1:9).
Reaction SMILES: COP([CH2:7][C:8]([O:10][CH3:11])=[O:9])(OC)=O.[H-].[Na+].[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C:16](=O)[CH2:15]2>C1COCC1>[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C:16](=[CH:7][C:8]([O:10][CH3:11])=[O:9])[CH2:15]2
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=C1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=C1CN2CCC1CC2
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(dimethoxyphosphoryl)acetate (2.70 g, 14.8 mmol) in THF (200 ml) at 0° C. was added NaH [60% dispersion in mineral oil](600 mg, 15.0 mmol). After 1 h of stirring, quinuclidin-3-one (2.00 g, 12.4 mmol) was added and the resultant mixture was stirred at room temperature for 18 h. The reaction was quenched with 50 ml water at 0° C. and the mixture was extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure to afford crude methyl 2-(quinuclidin-3-ylidene)acetate, which was used in next step without purification (1.2 g, 70%).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=1[C:26]([F:29])([F:28])[F:27]>C1(C)C=CC=CC=1>[CH2:9]([O:8][P:1]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=1[C:26]([F:27])([F:28])[F:29])(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: O=C(Nc1ccc(CBr)c(C(F)(F)F)c1)C(F)(F)F
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(NC(=O)C(F)(F)F)cc1C(F)(F)F)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6 ml of triethyl phosphite are added to a suspension of 10 g N-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide (obtainable according to WO 2005051366) in 60 ml of toluene. The mixture obtained is stirred for 18 hours at reflux, allowed to cool to rt and concentrated. The concentrate obtained is triturated in Et2O. [4-(2,2,2-Trifluoro-acetylamino)-2-trifluoromethyl-benzyl]-phosphonic acid diethyl ester is obtained in the form of a solid: ES-MS: 406.0 [M−H]−; tR=4.41 min (System 1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[OH:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[O:8][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1O
Temperature: 72.5 °C
Reaction time: 0.25 h

Procedure:
4-Nitrocatechol (5 g, 32.2 mmol) was dissolved in DMF (50 ml); thereafter, potassium carbonate (8.9 g, 64.5 mmol) was added and with heating at 70-75° C., ethyl bromoacetate (7.18 ml) was slowly added dropwise, followed by stirring at the same temperature for 15 min. The reaction solution was cooled to room temperature and filtered; after being concentrated under vacuum, the filtrate was diluted with a saturated aqueous solution of sodium bicarbonate (50 ml) and subjected to extraction with ethyl acetate (300 ml). The extracted organic layer was dried with magnesium sulfate and the solvent was evaporated. The resulting residue was purified by being subjected to column chromatography on silica gel using a 2:1 solvent system of n-hexane and ethyl acetate as an eluent. The fractions containing the product were collected and the solvent was evaporated to yield the end compound ethyl (2-hydroxy-4-nitrophenoxy)acetate (1.05 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][C:46](=[CH2:49])[CH2:47][NH2:48]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:48][CH2:47][C:46]([CH3:49])=[CH2:45])=[O:22])=[CH:16][CH:15]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: C=C(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C=C(C)CNC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2-methylallylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give 2′-methyl-N-(2-methylallyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][C:29]1([CH3:35])[CH2:31][CH:30]1[C:32](O)=[O:33]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([CH:30]3[CH2:31][C:29]3([CH3:35])[CH3:28])=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: CC1(C)CC1C(=O)O
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C3CC3(C)C)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and rac-2,2-dimethyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a colorless amorphous solid. MS (ESI): m/z=375.3 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([I:12])[C:3]=1[NH2:4].[N-:13]=[N+:14]=[N-].[Na+]>S(=O)(=O)(O)O.O>[I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([I:12])[C:3]=1[N:4]=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1c(I)cc([N+](=O)[O-])cc1I
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1c(I)cc([N+](=O)[O-])cc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 g of 2,6-diiodo-4-nitroaniline was dissolved in 20 ml of conc. sulfuric acid and cooled with ice. Sodium nitrite previously vacuum-dried was added to the solution in portions to effect the diazotization reaction at 0°-5° C. The reaction product was added dropwise to ice-water to dilute the sulfuric acid. A solution of 1.4 g of sodium azide in 10 cc of water was added dropwise to the mixture, stirred for about one hour, filtered and washed with water. After the recrystallization from ethanol followed by drying, 2,6-diiodo-4-nitroazidobenzene was obtained.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]1[CH2:13]CC[CH2:10][CH2:9]1.O>CC(CC)=O>[CH2:8]([C:9]1([CH3:10])[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][O:4]1)[CH3:13]
Reactant: C1CCCCC1
Reactant: OCCNCCO
Solvent: O
Solvent: CCC(C)=O
Product: CCC1(C)OCCN1CCO
Yield: 78 %

Procedure:
A mixture of 315 g (3 mols) of diethanolamine, 432 g (6 moles) of methylethylketone, and 100 ml of cyclohexane is stirred and heated to reflux using a Dean-Stark trap to separate the water formed. The mixture is stirred and refluxed for a total of 311/2 hours during which 54 ml of aqueous layer, 85% water and 15% methylethylketone by NMR, is collected (85% of the theoretical amount of water of reaction). The mixture is then concentrated and the residue distilled to give 373 g (78% yield) of product, b.p. 85°-88° C./2.5-3.0 mm Hg.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=[O:4].OC1C=C(C=CC=1)C(OCC)=O.OC1CCOC1.[C:31]1([P:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[C:44]1([P:37](=[O:4])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: CCOC(=O)c1cccc(O)c1
Agent: OC1CCOC1
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Diethyl azodicarboxylate (2.09 g) was added to a stirred mixture of ethyl 3-hydroxybenzoate (1.662 g), 3-hydroxytetrahydrofuran (0.881 g), triphenylphosphine (3.41 g) and THF (40 ml) which had been cooled to 0° C. The resultant mixture was allowed to warm to ambient temperature and was stirred for 18 hours. The mixture was evaporated and the residue was triturated under a 9:1 mixture of hexane and ethyl acetate. The solid triphenylphosphine oxide so formed was filtered off. The filtrate was evaporated and the residue was purified by column chromatography on silica using a 99:1 mixture of methylene chloride and methanol as eluent. There was thus obtained ethyl 3-(tetrahydrofuran-3-yloxy)benzoate (1.56 g); NMR Spectrum: (DMSOd6) 1.27 (t, 3H), 1.93 (m, 1H), 2.22 (m, 1H), 3.82 (m, 4H), 4.27 (m, 2H), 5.08 (m, 1H), 7.19 (m, 1H), 7.42 (m, 2H), 7.52 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]([C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42](O)=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:42](=[O:43])[CH2:41][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[O:34][CH3:33])[CH2:15][CH2:14]3)[N:10]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nc(C3CCNCC3)n(-c3ncccn3)n2)cc1
Reactant: COc1ccccc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1CC(=O)N1CCC(c2nc(-c3ccc(F)cc3)nn2-c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of INTERMEDIATE 9 HCl salt (15.0 mg, 0.035 mmol) and triethylamine (22.9 mg, 0.23 mmol) in DMF (0.25 ml) was added (2-methoxyphenyl)acetic acid (7.8 mg, 0.045 mmol), followed by addition of HATU (17.2 mg, 0.045 mmol). After stirring at ambient temperature for 1.5 hour, the reaction mixture was quenched with 2 mL of a mixture of 1,4-dioxane and water (1:1). The mixture was purified by RP-HPLC (10 to 100% ACN/Water, both containing 0.1% TEA) to give the title compound as a white powder after lyophilization. LC-MS (m/z): 473.11 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH2:10][Cl:11])[CH2:8][S:9][C@H:4]12.C[Si](C)(C)NC(=O)C.CS([O:42][C:43](=O)[C:44]([C:51]1[N:55]=[C:54]([NH2:56])[S:53][N:52]=1)=[N:45][O:46][CH2:47][C:48]([OH:50])=[O:49])(=O)=O.C(OCC)(=O)C>O1CCCC1.O>[NH2:56][C:54]1[S:53][N:52]=[C:51]([C:44](=[N:45][O:46][CH2:47][C:48]([OH:50])=[O:49])[C:43]([NH:2][C@@H:3]2[C:28](=[O:29])[N:5]3[C:6]([C:12]([O:14][CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:13])=[C:7]([CH2:10][Cl:11])[CH2:8][S:9][C@H:4]23)=[O:42])[N:55]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CS(=O)(=O)OC(=O)C(=NOCC(=O)O)c1nsc(N)n1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc(C(=NOCC(=O)O)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)ns1
Yield: 53.4 %

Procedure:
To a solution of benzhydryl 7β-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (22.6 g) and N-trimethylsilylacetamide (25.0 g) in tetrahydrofuran (250 ml) was added 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetic methanesulfonic anhydride (syn isomer) (19.8 g) at 0°-5° C. under stirring. The stirring was continued for an hour at the same temperature. The reaction mixture was poured into a mixture of ethyl acetate (500 ml) and water (500 ml). The organic layer was separated, washed with water twice and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated in vacuo. To the residue was added diethyl ether and then the resulting precipitates were collected by filtration to give benzhydryl 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (17.2 g).