Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[F:2][C:3]1[C:11]([O:12][C:13]2[C:14]3[CH:21]=[C:20]([C:22]4[CH:30]=[CH:29][C:25]([C:26]([O-:28])=O)=[CH:24][CH:23]=4)[NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:31])[NH:7]2.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH3:33].C(OP(C#N)(=O)OCC)C>CN(C=O)C.CCOC(C)=O>[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([C:26]([C:25]2[CH:24]=[CH:23][C:22]([C:20]3[NH:19][C:15]4[N:16]=[CH:17][N:18]=[C:13]([O:12][C:11]5[C:3]([F:2])=[C:4]6[C:8](=[CH:9][CH:10]=5)[NH:7][C:6]([CH3:31])=[CH:5]6)[C:14]=4[CH:21]=3)=[CH:30][CH:29]=2)=[O:28])[CH2:36][CH2:35]1)[CH3:33]
Reactant: CCN1CCNCC1
Reactant: Cc1cc2c(F)c(Oc3ncnc4[nH]c(-c5ccc(C(=O)[O-])cc5)cc34)ccc2[nH]1
Agent: CCOP(=O)(C#N)OCC
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN1CCN(C(=O)c2ccc(-c3cc4c(Oc5ccc6[nH]c(C)cc6c5F)ncnc4[nH]3)cc2)CC1
Reaction time: 1 h

Procedure:
To 340 mg (0.83 mMol) 4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoic acid lithium salt in 5 ml of DMF under N2-atmosphere, 0.38 ml (3 mMol) of N-ethylpiperazine and 0.31 ml (95%; 2 mMol) of diethyl-cyanphosphonate are added at 0° C. After 60 min, the suspension is diluted with EtOAc and washed with saturated NaHCO3-solution, water and brine. The aqueous layers are re-extracted twice with EtOAc, the organic layers dried (Na2SO4) and concentrated after adding SiO2. The resulting powder is put on top of a chromatography column (SiO2) and the title compound eluted with EtOAc/methanol/NH3conc. 80:20:1; HPLC (conditions see Examples 67-78) tR=10.4 min; MS-ES+: (M+H)+=499.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].Cl.[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][N:37]([C:42]2[CH:55]=[CH:54][C:45]3[N:46]([CH2:50][C:51](O)=[O:52])[C:47](=[O:49])[O:48][C:44]=3[CH:43]=2)[S:38]([CH3:41])(=[O:40])=[O:39])[CH2:31][CH2:30]1.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:51](=[O:52])[CH2:50][N:46]1[C:45]2[CH:54]=[CH:55][C:42]([N:37]([CH2:36][CH2:35][N:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:43][C:44]=2[O:48][C:47]1=[O:49]
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)oc(=O)n2CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)oc(=O)n2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reaction time: 8 h
Yield: 37.8 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (281 mg, 0.669 mmol), 2-(6-(N-(2-morpholinoethyl)-methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid hydrochloride (350 mg, 0.803 mmol), EDC (192 mg, 1.004 mmol) and DMAP (204 mg, 1.673 mmol) were dissolved in dry DCM (8 ml), and the mixture was reacted at room temperature for 5 hours. Additional EDC (128 mg, 0.669 mmol) and DMAP (82 mg, 0.669 mmol) were added, and the reaction was stirred at the same temperature overnight. Thus, the mixture was treated with 1N HCl (30 ml) and extracted with DCM (2×100 ml). The organic phase was washed with brine and dried over Na2SO4; the solvent was removed under reduced pressure and the resulting crude was purified by flash chromatography (DCM/MeOH 98/2 to 90/10) yielding (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-(N-(2-morpholinoethyl)methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetoxy)ethyl)pyridine 1-oxide (203 mg, 0.253 mmol, 37.8% yield, MS/ESI+ 801.15 [MH]+, [αD]=−20.63, c=0.505, DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (s, 2H), 7.52 (d, 1H), 7.27 (dd, 1H), 7.22 (d, 1H), 7.20 (d, 1H), 7.11 (d, 1H), 6.97 (dd, 1H), 7.08 (t, 1H), 6.04 (dd, 1H), 4.86 (d, 1H), 4.72 (d, 1H), 3.94 (d, 2H), 3.74 (t, 2H), 3.46-3.57 (m, 4H), 3.38 (dd, 1H), 3.22 (dd, 1H), 3.09 (s, 3H), 2.22-2.44 (m, 6H), 1.16-1.31 (m, 1H), 0.50-0.66 (m, 2H), 0.28-0.46 (m, 2H).
Reaction SMILES: COC1C=CC(C([O:22][C@@H:23]2[C@@H:27]([CH2:28]OC(C3C=CC=CC=3)(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)[O:26][C@@H:25]([N:53]3[CH:60]=[CH:59][C:57](=[O:58])[NH:56][C:54]3=[O:55])[C@@H:24]2[F:61])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.C(O)(=O)C>CO>[F:61][C@@H:24]1[C@H:23]([OH:22])[C@@H:27]([CH3:28])[O:26][C@H:25]1[N:53]1[CH:60]=[CH:59][C:57](=[O:58])[NH:56][C:54]1=[O:55]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](F)[C@@H]2OC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](F)[C@@H]1O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The residue obtained in the above described (iv) was dissolved in MeOH, 100 mL of 80% acetic acid was then added thereto. After stirring at 80° C. for 6 hours, the reaction solution was concentrated, and dissolved in 150 mL of H2O. Subsequently, extraction and washing were carried out three times with 150 mL each of CHCl3, then the solvent of the aqueous layer was evaporated. The resulting residue was dissolved in 15 mL of chloroform, then isolated and purified by silica gel column chromatography (chloroform: methanol=1:0 to 7:1). The solvent was evaporated to obtain white crystal of the compound(3) (yield: 1.68 g, 6.8 mmol, 58%).
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.CN(C)C=O.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[S:1]1[C:5]2[C:6]([C:10]([Cl:20])=[O:12])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc2nnsc12
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cccc2nnsc12

Procedure:
290 g of benzo-1,2,3-thiadiazole-7-carboxylic acid are suspended in 1.6 l of toluene, 3.5 ml of dimethylformamide and 129 ml of thionyl chloride are added and the mixture is stirred at 80°-90° C., the suspension turning into a solution as the release of gas progresses. When the reaction has ended, the solution is cooled and filtered over a little Hyflo, the residue is rinsed with toluene and the filtrate is evaporated. 297 g (93%) of crude acid chloride, which can be further reacted directly, result.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4].[CH3:23][CH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=O>>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][N:18]([CH:25]4[CH2:26][CH2:27][CH2:28][CH:24]4[CH3:23])[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: CC1CCCC1=O
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCCC2C)CC3)nc1

Procedure:
Example 224 (E224) was prepared from N-methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) and 2-methyl cyclopentanone using the method described for Example 223; MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:26][O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:15]=1)[CH3:25]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCOc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1.2 g (0.030 mol) of 60% sodium hydride in 100 mL of toluene was added 6.12 g (0.030 mol) of 4-(benzyloxy)phenol and the reaction was stirred at room temperature for 30 minutes followed by the addition of 5.85 g (0.030 mol) of ethyl 3-bromobutyrate. The resulting mixture was heated to reflux overnight and then filtered. The filtrate was washed with 0.5N sodium hydroxide solution, 3% sodium carbonate solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 5.45 g of the bis-ether as a white solid. Electrospray Mass Spec: 314.8 (M+H)+
Reaction SMILES: CCCCCCCCCCCCCCCCCC(N[C@H]([C@H](O)/C=C/CCCCCCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@@:68]3(C(O)=O)[O:73][C@@H:72]([C@H:74](O)[C@H:75](O)[CH2:76]O)[C@H:71](NC(C)=O)[C@@H:70]([OH:84])[CH2:69]3)[C@H]2O)[C@H](O)[C@H]1O)=O.[CH2:108]([OH:110])[CH3:109]>>[CH3:76][C:75]1[C:74]2[CH:72]=[CH:71][C:70]([OH:84])=[CH:69][C:68]=2[O:73][C:108](=[O:110])[CH:109]=1
Reactant: CCO
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@]3(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC
Product: Cc1cc(=O)oc2cc(O)ccc12
Reaction time: 0.5 h

Procedure:
The saliva of each experimental group of Test Example 1 in the present specification was used to examine inhibitory activity against cholera toxin binding. 200 μl of an ethanol solution containing 0.1% ganglioside GM1 (w/v) was added to a 96-well plate for ELISA test. Then, the ganglioside GM1 was adsorbed thereonto by air-drying. The saliva of each experimental group was diluted 10 times with PBS containing 1% bovine serum albumin (BSA) and then reacted for 1 hour by the addition of a biotin-conjugated cholera toxin. 100 μl of the reaction solution was added to the plate for ELISA test, and the plate was left for 30 minutes. Then, the supernatant was removed. The plate for ELISA test was washed several times with PBS containing 0.05% Tween 20. Biotin-binding β-galactosidase was added thereto. The plate for ELISA test was left for a given length of time. Then, the supernatant was removed. The plate for ELISA test was washed several times again with PBS containing 0.05% Tween 20, and the contents in the plate were reacted for 30 minutes by the addition of 4-methylumbelliferyl galactose. Then, 4-methylumbelliferone produced was measured with a fluorophotometer (excitation wavelength: 360 nm, measurement wavelength: 460 nm). Then, an inhibition rate was calculated according to the following formula: Inhibition rate(%)={1−(A/B)}×100, wherein
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:24]2[C:25]([F:37])=[C:26]([NH:30]C(=O)OCC=C)[CH:27]=[CH:28][CH:29]=2)[CH:5]=[CH:4][N:3]=1.C([SnH](CCCC)CCCC)CCC.O>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:30][C:26]1[C:25]([F:37])=[C:24]([C:9]2[N:10]=[C:11]([C:13]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)NC(=O)OC(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a solution of 2-propen-1-yl (3-{5-(2-chloro-4-pyrimidinyl)-2-[1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-methylethyl]-1,3-thiazol-4-yl}-2-fluorophenyl)carbamate (1.28 g, 2.336 mmol). tri-n-butyltin hydride (0.624 mL, 2.336 mmol) in dichloromethane (DCM) (50 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.135 g, 0.117 mmol) followed by water (0.2 mL). After 30 min, the reaction was concentrated. The residue was purified via chromatography on silica gel to obtain the title compound (0.81 g 74% yield). MS (ESI): 464.1 [M+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([CH:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH3:53])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([CH:45]4[CH2:46][CH2:47][N:48]([CH2:51][CH2:52][CH3:53])[CH2:49][CH2:50]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCCN1CCC(c2ccc(N)c(OC)c2)CC1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCN1CCC(c2ccc(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OC)c2)CC1
Temperature: 120 °C
Yield: 68.4 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), a different batch of 2-(methyloxy)-4-(1-propyl-4-piperidinyl)aniline (48 mg, 0.19 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 24 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (92 mg, 0.13 mmol, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.37 (d, J=6.23 Hz, 1H), 8.50 (s, 1H), 8.24 (d, J=5.31 Hz, 1H), 8.10 (d, J=2.01 Hz, 1H), 7.76 (dd, J=8.61, 2.20 Hz, 1H), 7.66 (dd, J=18.77, 8.52 Hz, 2H), 7.34-7.45 (m, 2H), 7.27 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.92-6.99 (m, 2H), 6.78 (dd, J=8.06, 1.65 Hz, 1H), 6.58 (d, J=5.13 Hz, 1H), 3.97 (s, 3H), 3.81 (s, 3H), 2.87-2.97 (m, J=10.80 Hz, 2H), 2.39-2.46 (m, 1H), 2.17-2.27 (m, 2H), 1.86-1.97 (m, 2H), 1.64-1.75 (m, 4H), 1.38-1.48 (m, 2H), 0.84 (t, J=7.23 Hz, 3H). MS (ESI): 704 [M+H]+.
Reaction SMILES: CS(O[CH:6]1[CH2:10][O:9][CH:8]2[CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[CH2:12][O:13][CH:7]12)(=O)=O.[N:25]([Na])=[N+:26]=[N-:27]>CN(C=O)C.C(Cl)Cl>[N:25]([CH:6]1[CH:7]2[O:13][CH2:12][CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[CH:8]2[O:9][CH2:10]1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=N[Na]
Reactant: CS(=O)(=O)OC1COC2C1OCC2N1C(=O)c2ccccc2C1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NC1COC2C1OCC2N1C(=O)c2ccccc2C1=O
Temperature: 140 °C

Procedure:
To a solution of 6-(1,3-dioxoisoindolin-2-yl)hexahydrofuro[3,2-b]furan-3-yl methanesulfonate (2.80 g, 7.9 mmol) in DMF (60 mL) was added azido sodium (2.16 g, 33.2 mmol). The reaction was allowed to warm to 140° C. for 23 h. The solution was diluted with CH2Cl2 (100 mL), washed with water (100 mL×3) and dried over anhydrous Na2SO4, and then concentrated in vacuo to give the crude product. The product was used for next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:17](OC=C)(=[O:19])[CH3:18].C(OCCCCCCCC)=C>C1(C)C=CC=CC=1>[C:17]([O:16][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:19])[CH3:18]
Reactant: CCCCCCCCO
Reactant: C=COC(C)=O
Agent: C=COCCCCCCCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCOC(C)=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (0.01 mmol) and triethylamine (0.6 mmol) in toluene (1.0 ml), 1-octanol (130 mg, 1 mmol) and vinyl acetate (2 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 2 hours. The reaction mixture was analyzed by gas chromatography to find that 1-octyl vinyl ether and octyl acetate were produced in yields of 19% and 2%, respectively, with a conversion from 1-octanol of 30%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:24])[NH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Si:27]([O:34][CH:35]([C:45]([F:48])([F:47])[F:46])[CH:36]([NH:40][C:41](=[O:44])[CH2:42]I)[CH:37]([CH3:39])[CH3:38])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O.Cl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:24])[N:14]([CH2:42][C:41]([NH:40][CH:36]([CH:37]([CH3:39])[CH3:38])[CH:35]([O:34][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:45]([F:46])([F:48])[F:47])=[O:44])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)CI)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reactant: O=C(Nc1ccc(-c2ccccc2)[nH]c1=O)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 0.25 h
Yield: 28.3 %

Procedure:
3-Benzyloxycarbonylamino-6-phenylpyrid-2-one (1.7 g) was added to a suspension of NaH (0.14 g) in dry dimethylformamide (50 mL). After 15 min stirring, the turbid, orange solution was treated with N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-iodoacetamide (2.65 g) and the mixture was stirred overnight. The mixture was diluted with 10% hydrochloric acid (125 mL) and extracted with ethyl acetate (2 times 150 mL). The combined extracts were washed with 10% hydrochloric acid and water (twice), dried and evaporated to an orange-brown glass. Purification by flash chromatography (gradient elution, 1%-4% ethyl acetate in dichloromethane) and overnight drying under vacuum yielded the N-alkylated product 2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (0.97 g, 28%); TLC: Rf =0.35, dichloromethane:ethyl acetate (97:3); 300 MHz NMR: 0.08 (s,3), 0.10 (s, 3), 0.81 (d,3, J=6.6), 0.86 (s,9), 0.93 (d,3, J=6.6), 1.67-1.78 (m,1), 3.81 (t,1, J=10), 4.22-4.40 (m,2), 4.64 (broad d,1, J=15), 5.19 (s,2), 6.22 (d,1, J=7.6), 7.33-7.48 (m,10), 7.63 (d,1, J=9.9), 7.92 (d,1, J=7.6), 8.53 (s,1). Also obtained was the O-alkylated product 2-(3-benzyloxycarbonylamino-6-phenylpyrid-2-yloxy)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (2.11 g, 62%); TLC: Rf =0.61, dichloromethane:ethyl acetate (97:3), 300 MHz NMR: 0.01 (s,3), 0.07 (s,3), 0.75 (s,9), 0.77 (d, 3, J=6.6), 0.89 (d,3, J=6.6), 1.67-1.81 (m,1), 3.84 (t,1, J=10), 4.26 (m,1), 4.81 (d,1, J=15), 5.14 (d,1, J=15), 5.20 (s,2), 7.35-7.48 (m,9), 7.62 (d,1, J=8), 7.99 (dd,2, J=1.6, J=8.4), 8.12 (d,1, J=8), 9.31 (s,1); MS: m/z=646(M+1). (A mixed fraction (0.25 g, 7%) was also obtained).
Reaction SMILES: [F:1][C:2]([F:19])([CH:8]([OH:18])[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:19])([CH:8]([O:18][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)C(OS(=O)(=O)c1ccc(C)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.2 %

Procedure:
To a solution of ethyl 2,2-difluoro-3-hydroxy-3-(4-nitrophenyl)propanoate (800 mg, 2.91 mmol) in pyridine (20 mL) was added dropwise p-toluenesulfonyl chloride (665 mg, 3.49 mmol), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-40% ethyl acetate/hexane) to give the title compound (1.09 g, yield 99%) as a colorless oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([OH:53])=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[NH:54]([C:56](=[O:70])[CH2:57][CH:58]1[CH2:61][CH:60]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])[CH2:59]1)[NH2:55]>CN(C=O)C>[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([NH:55][NH:54][C:56](=[O:70])[CH2:57][CH:58]1[CH2:61][CH:60]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:66])([CH3:67])[CH3:68])[CH2:59]1)=[O:53])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)NC1CC(CC(=O)NN)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
HATU (1.6 g, 4.3 mmol) and DIPEA (0.93 g, 7.2 mmol) were added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (1.0 g, 3.6 mmol), tert-butyl 3-(2-hydrazinyl-2-oxoethyl)cyclobutylcarbamate (0.97 g, 3.9 mmol) in DMF (10 mL) at. The reaction mixture was stirred at 0° C. for 1 hr. The mixture was quenched with saturated sodium chloride (50 mL) and the organic layer was separated. The water layer was exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (50% EtOAc/petroleum ether) to afford tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclobutylcarbamate (1.5 g, 88%). ESI-MS (EI+, m/z): 502 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14](O)[CH2:15][S:16][C@H:11]12)=[O:8].CN(C=O)C.C(Cl)(=O)C([Cl:41])=O.Cl>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([Cl:41])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reaction time: 4 h

Procedure:
To a solution of 439 mg. (0.93 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate in 4.4 ml. of DMF cooled in an ice bath was added dropwise 118 mg. (0.07 ml., 0.93 mmole) of oxalyl chloride. The reaction mixture was allowed to stand for 4 hours at room temperature and was then poured into a mixture of aqueous 5% hydrochloric acid and ethyl acetate. The organic layer was separated and was washed sequentially with 5% hydrochloric acid, water and a saturated solution of sodium chloride. The washed layer was dried and evaporated to dryness to yield the reaction product, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate as an amorphous solid. The product was obtained crystalline by triturating the amorphous residue with ether. Yield 360 mg. The infrared spectrum and NMR spectrum of the crystalline product were consistent with the spectra of authentic material.