Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([O:27]CC)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].CCO>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=[O:26])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C(=O)NCc2ccc(C)nc2)cc(-c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylate (1.02 g, 2.62 mmol), lithium hydroxide (310 mg, 13 mmol), EtOH (100 mL), and water (10 mL) was stirred at rt overnight. LC-MS indicated completion of the reaction. The solvent was removed in vacuo and the residue was treated with water (50 mL) and acidified with 1N aq. HCl to pH=4. The precipitated solids were collected by filtration, washed with water, and dried to yield a white solid.
Reaction SMILES: [O:1]=[P:2]([Cl:5])(Cl)[Cl:3].N1C=CC=CC=1.[CH2:12]([OH:17])[C:13]([F:16])([F:15])[F:14]>C1(C)C=CC=CC=1>[P:2]([Cl:5])([Cl:3])(=[O:1])[O:17][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: OCC(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=P(Cl)(Cl)OCC(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 17.3 g (0.113 mol) of POCl3 in 50 mL of toluene held at 0° C. was added 7.9 g (0.10 mol) of pyridine, followed by addition of 10.0 g (0.10 mol) of trifluoroethanol, at a rate to maintain the temperature of the mixture at 0°-10° C. The mixture was stirred one hour at ice bath temperature, and then overnight at room temperature. After filtering, the solution was distilled to give the desired 2,2,2-trifluoroethyl phosphorodichloridate, bp 140°-146° C. The dichloridate, 4.5 g (0.21 mol) was treated with 10 g NH3 in 50 mL CH2Cl2 at -40° C. After warming to room temperature, the product was filtered and purified by Soxhlet extraction with CH2Cl2 for two days. After drying over P2O5, the 2,2,2-trifluoroethyl phosphorodiamidate had mp 142°-144° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:27])=[C:8](C(OCC)=O)[C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:28]1[CH:29]=[N:30][NH:31][CH:32]=1.[OH-].[Na+].C(O)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>CS(C)=O.O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:27])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:28]1[CH:32]=[N:31][NH:30][CH:29]=1
Reactant: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)c(Br)c2c1NS(=O)(=O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cn[nH]c3)sc2n1
Temperature: 150 °C
Yield: 42.5 %

Procedure:
Alternatively, a mixture of ethyl 3-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methyl-2-(1H-pyrazol-4-yl)thieno[2,3-b]pyridine-5-carboxylate (Description 74) (8.2 g, 14.75 mmol) in DMSO (150 mL) and aqueous NaOH (5M) (11.80 mL, 59.0 mmol) was heated at 150° C. for ca. 15 min. Extra aqueous NaOH (5M) (11.80 mL, 59.0 mmol) was added and the mixture heated at 150° C. for another 45′ min. After cooling to RT, the mixture was diluted with water (200 mL) and acidified with formic acid (ca. pH 4-5). The mixture was then extracted with 20% MeOH/DCM (75 mL×5) and the combined organics dried and concentrated. Water (100 mL) was added to the residue and a precipitate crashed-out which was collected by filtration and rinsed with water (50 mL×3). The solid was dried and subsequently taken-up in diphenyl ether (100 mL, 629 mmol) and DMSO (20 mL) and the mixture heated at 200° C. for ca. 35 min. After cooling to RT, the mixture was purified on silica, eluting with a gradient of 0-100% ethyl acetate in cyclohexane followed by 10% MeOH in DCM, to give the title compound (3.03 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[O:15][C:13]1[CH:14]=[CH:9][N:10]=[C:11]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH:12]=1
Reactant: Cc1csc(N)n1
Reactant: Fc1cccc(F)c1Oc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1csc(Nc2cc(Oc3c(F)cccc3F)ccn2)n1
Yield: 39.4 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (0.284 g, 2.48 mmol), 2-chloro-4-(2,6-difluorophenoxy)pyridine (0.600 g, 2.48 mmol), potassium phosphate (0.580 g, 2.73 mmol), Pd2(dba)3 (0.114 g, 0.124 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.072 g, 0.124 mmol) were reacted to provide N-(4-(2,6-difluorophenoxy)pyridin-2-yl)-4-methylthiazol-2-amine (0.312 g, 39% yield). 1H NMR (d6-DMSO) δ 11.03 (s, 1H), 8.20 (d, 1H), 7.36-7.50 (m, 3H), 6.60-6.63 (m, 2H), 6.54 (s, 1H), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[H-].[Na+].[F:19][C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[C:22](F)[N:21]=1>CN(C)C=O>[F:19][C:20]1[N:21]=[C:22]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)[CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:27])[F:28]
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Reactant: Fc1ccc(C(F)(F)F)c(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)(F)F)c(F)n2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (1.008 mmol; 213.0 mg) in Dimethylformamide (10 mL) at 0° C. was added sodium hydride (60% in mineral oil; 1.210 mmol; 48.40 mg). The resulting mixture was stirred for 10 min. 2,6-difluoro-3-(trifluoromethyl)pyridine (1.008 mmol; 184.6 mg) was then added. The reaction was stirred and allowed to warm to room temperature and stirred for 4 hours. The mixture was quenched with water, and extracted with EtOAc. The organic layer was washed with brine, and then concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in Heptane. 1-[6-fluoro-5-(trifluoromethyl)-2-pyridyl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine was obtained as the most abundant isomer (173.6 mg, 46%).
Reaction SMILES: I(O)(=O)(=O)=[O:2].[CH:6]([C:8]1[O:9][C:10]2[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=[C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:11]=2[CH:12]=1)=[O:7]>CC#N.C(OCC)(=O)C.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Cr](F)([O-])(=O)=O>[CH2:20]([O:19][C:17]([C:15]1[CH:14]=[C:13]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[C:11]2[CH:12]=[C:8]([C:6]([OH:2])=[O:7])[O:9][C:10]=2[CH:16]=1)=[O:18])[CH3:21]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C=O)oc2c1
Agent: O=[Cr](=O)([O-])F
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C(=O)O)oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
To 10 mL of acetonitrile was added periodic acid (232 mg, 1.02 mmol), and the solution was stirred vigorously at room temperature for 15 min. Ethyl 2-formyl-4-(4-(methylsulfonyl)phenoxy)-benzofuran-6-carboxylate (360 mg, 0.927 mmol) was then added at 0° C. followed by the addition of pyridium fluorochromate (3.69 mg, 0.0185 mmol) in CH3CN (1 mL). The reaction was stirred at 0° C. for 1 hour. The reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried and concentrated to give the title compound (355 mg, 95%) as an orange solid. The crude product was used in the next step without further purification. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.16 Hz, 3 H) 3.09 (s, 3 H) 4.41 (q, J=7.16 Hz, 2 H) 7.12-7.22 (m, 2 H) 7.55 (d, J=1.13 Hz, 1 H) 7.63 (d, J=1.13 Hz, 1 H) 7.92-8.02 (m, 2 H) 8.17 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CN1C(=O)N(C)CCC1.C(N(CC)CC)C.[CH2:31]([N:33]([CH2:37][CH3:38])[C:34](Cl)=[S:35])[CH3:32]>O>[CH2:11]([N:10]([CH2:13][CH3:14])[C:8](=[O:9])[C:3]1[C:2]([O:1][C:34](=[S:35])[N:33]([CH2:37][CH3:38])[CH2:31][CH3:32])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:12]
Reactant: CCN(CC)C(=S)Cl
Reactant: CCN(CC)C(=O)c1ncccc1O
Solvent: CN1CCCN(C)C1=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ncccc1OC(=S)N(CC)CC
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
258.3 g (1.33 mol) of 3-hydroxy-N,N-diethylpicolinamide are introduced into 1 l of dimethylpropyleneurea and 213.2 ml (1.53 mol) of triethylamine at 0° C., and 222 g (1.464 mol) of diethylthiocarbamoyl chloride are introduced in the form of a solid. After the reaction mixture has been stirred for 2 hours at 0° C., it is poured into 2 l of water and extracted three times using ethyl acetate, the ethyl acetate phases are washed five times using 500 ml of water in each case, and the combined organic phases are dried over Na2SO4 and concentrated in vacuo at 60° C. Recrystallization from Et2O/hexane gives 341 g (83%) of brown crystals, m.p. 70°-72° C.
Reaction SMILES: [N:1]([C@@H:4]([C:24]1[C:25]([CH3:34])=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][CH2:27]2)[CH2:5][N:6]1[CH2:23][CH2:22][C:9]2([C:13](=[O:14])[N:12]([C:15]3[CH2:16][O:17][C:18](=[O:21])[C:19]=3[CH3:20])[CH2:11][CH2:10]2)[CH2:8][CH2:7]1)=[N+]=[N-].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[NH2:1][C@@H:4]([C:24]1[C:25]([CH3:34])=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][CH2:27]2)[CH2:5][N:6]1[CH2:7][CH2:8][C:9]2([C:13](=[O:14])[N:12]([C:15]3[CH2:16][O:17][C:18](=[O:21])[C:19]=3[CH3:20])[CH2:11][CH2:10]2)[CH2:22][CH2:23]1
Reactant: CC1=C(N2CCC3(CCN(C[C@@H](N=[N+]=[N-])c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(N2CCC3(CCN(C[C@@H](N)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-8-(2-azido-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (200 mg, 0.43 mmol) in a mixed solvent of tetrahydrofuran and water (v:v, 12:1, 20 mL) was added triphenylphosphine (225 mg, 0.86 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed by evaporation and the residue was purified by preparative TLC (dichloromethane: methanol=10:1) to afford the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][O:23][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 15.1, 5-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol and methane sulfonyl chloride were converted to yield Methanesulfonic acid 5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester light brown oil, MS: 369 (M).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.[N+:11]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12].[N+:24]([O-])([OH:26])=[O:25].ClC(Cl)C>>[N+:24]([C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]=1[N+:11]([O-:13])=[O:12])([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cccc2ccccc12
Reactant: O=[N+]([O-])O
Solvent: c1ccc2ccccc2c1
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1ccc2ccccc2c1[N+](=O)[O-]

Procedure:
DE-OS-24 53 529 describes the production of dinitronaphthalenes by nitration of naphthalene or 1-nitronaphthalene with nitric acid in an organic solvent, e.g., dichloroethane, with the azeotropic removal of the water of reaction. This process yields dinitronaphthalene in high yields, but without influencing the isomer ratio.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:18]3[N:19]([C:24]([C:27]#[N:28])=[CH:25][N:26]=3)[N:20]=[C:21](Cl)[CH:22]=2)=[N:12]1)(C(C)(C)C)(C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[C:36]([N:38]2[C:42]([CH3:43])=[N:41][N:40]=[N:39]2)[CH:37]=1)[NH2:34].C(P(C(C)(C)C)C1(C)CC1(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].CO>[OH:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:18]3[N:19]([C:24]([C:27]#[N:28])=[CH:25][N:26]=3)[N:20]=[C:21]([NH:34][C:33]3[CH:35]=[C:36]([N:38]4[C:42]([CH3:43])=[N:41][N:40]=[N:39]4)[CH:37]=[C:31]([O:30][CH3:29])[CH:32]=3)[CH:22]=2)=[N:12]1
Reactant: COc1cc(N)cc(-n2nnnc2C)c1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(Nc2cc(Cl)nn3c(C#N)cnc23)n1
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc(Nc2cc(Nc3ccn(CCO)n3)c3ncc(C#N)n3n2)cc(-n2nnnc2C)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 3.84 %

Procedure:
A suspension of 12A (39 mg, 0.093 mmol), 3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)aniline (28.7 mg, 0.14 mmol), and di-tert-butyl (1-methyl-2,2-diphenylcyclopropyl) phosphine (6.58 mg, 0.019 mmol) in toluene (0.75 mL) was purged with nitrogen. Allylpalladium (II) chloride dimer (3.41 mg, 9.3 μmol) and sodium tert-butoxide (10.76 mg, 0.11 mmol) were added, and the reaction mixture was purged with nitrogen and heated at 100° C. After 15 minutes, the reaction mixture was concentrated, suspended in water (50 mL), extracted with 10% isopropanol/dichloromethane (3×25 mL), dried over Na2SO4, and concentrated. The crude was purified with silica gel chromatography (stepwise gradient, 20 to 50% ethyl acetate/hexanes to neat ethyl acetate). The fractions were concentrated, dissolved in dichloromethane (2 mL) and treated with TFA (2 mL). After 3 hours, the reaction mixture was concentrated, purified using reverse phase HPLC, and lyophilized with 1.0 N HCl to isolate Example 12, (2.1 mg, 3.84% yield) as a tan solid. HPLC: Rt=1.65 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 2 min. gradient, flow rate=5 mL/min., detection at 254 nm). MS (ES): m/z=473.06 [M+H]+. 1H NMR (500 MHz, methanol-d3) δ ppm 8.03 (1H, s), 7.86 (1H, s), 7.61 (1H, d, J=1.83 Hz), 7.51 (1H, s), 7.47 (1H, s), 6.68-6.89 (1H, m), 6.13 (1H, d, J=2.29 Hz), 4.23 (2H, t, J=5.27 Hz), 3.97 (2H, t, J=5.27 Hz), 3.94 (3H, s), 2.69 (3H, s).
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:11].[CH3:12][Si:13]([CH2:16][CH2:17][O:18][CH2:19]Cl)([CH3:15])[CH3:14].[H-].[Na+]>CN(C=O)C>[I:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:19][O:18][CH2:17][CH2:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1ccc2[nH]cnc2c1I
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(ncn2COCC[Si](C)(C)C)c1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 4-Iodo-5-methyl-1H-benzoimidazole (100 mg, 0.39 mmol, Example 287: step a) and SEMCl (71 mg 0.43 mmol) in 2 mL of DMF under Ar was added NaH (11 mg, 0.43 mmol). The mixture was stirred at RT for 4 h and purified directly by PTLC (25% EtOAc/hexane) to give 122 mg (81%) of product as a colorless oil: 1HMR (CDCl3; 400 MHz) δ 7.95 (s, 1H), 7.37 (d, 1H, J=8.4 Hz), 7.21 (d, 1H, J=8.4 Hz), 5.48 (s, 2H), 3.47 (t, 2H, J=8.3 Hz), 2.59 (s, 3H), 0.89 (t, 2H, J=8.3 Hz), −0.06 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C14H21IN2OSi, 389.1 (M+H), found 389.0.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6](=[O:9])[CH2:7][CH3:8].[C:10]([O:17][CH2:18][CH3:19])(=[O:16])[C:11]([O:13]CC)=O>>[O:13]=[C:11]([CH2:5][C:6](=[O:9])[CH2:7][CH3:8])[C:10]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(C)=O
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)CC
Temperature: -5 °C
Reaction time: 8 h

Procedure:
To a solution of sodium ethoxide (2.33 g, 34 mmol) in absolute alcohol (40 mL) was added a mixture of 2-butanone (2.45 g, 34 mmol) and diethyl oxalate (5 g, 34 mmol) dropwise at −5° C. The reaction mixture was stirred at −5° C. overnight and then concentrated. The resulting residue was partitioned between water (20 mL) and ethyl acetate (70 mL*3). The aqueous layer was acidified to pH 2 with dilute H2SO4 and then extracted with ethyl acetate (50 ml*3). The combined organic phase was dried over anhydrous Na2SO4, The organic solvent was evaporated in vacuo, and the residue was used directly in the next step without further purification.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:16])[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:6]=2[O:5]1.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:1][C:10]1[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:6]2[O:5][C:4]([CH3:16])([CH3:3])[CH2:8][C:7]=2[CH:9]=1
Reactant: CC1(C)Cc2cccc(C(=O)O)c2O1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(C)Cc2cc(Br)cc(C(=O)O)c2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using a dropping funnel, bromine (0.8 mL, 15.6 mmol) in acetic acid (6 mL) was added to a solution of 2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (1 g, 5.20 mmol) in acetic acid at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. A 2M solution of sodium sulfite was added until all of the red color disappeared. The volatiles were removed in vacuo and dichloromethane was added and the layers separated. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (667).
Reaction SMILES: [C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([F:18])[CH:12]=2)[C:6](=[O:19])[NH:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:26]([O:32][C@@H:33]1[C@@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[O:35][C@@H:34]1Br)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(#N)C.O1CCCC1>[C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([F:18])[CH:12]=2)[C:6]([O:19][C@@H:34]2[O:35][C@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:49])([CH3:50])[CH3:51])[C@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:42])([CH3:43])[CH3:44])[C@H:33]2[O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(=O)n1[nH]c(=O)c(Cc2ccc(C)c(F)c2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccc(C)c(F)c2)c1C
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To a suspension of 1-acetyl-4-[(3-fluoro-4-methyl-phenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one (0.32 g) in acetonitrile (3 mL) and tetrahydrofuran (1 mL) was added potassium carbonate (0.253 g) under stirring at room temperature. After stirring the mixture at 50° C. for 1 hour, 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (0.849 g) was added to the mixture. The mixture was stirred at 50° C. for 2 hours. After the reaction completed, the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/10 to 1/5) to give 1-acetyl-4-[(3-fluoro-4-methyl-phenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.884 g).
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:42](COCC[Si](C)(C)C)[CH:41]=[N:40][C:5]=2[C:6]([CH2:31][C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:7][C:8]=1[NH:9][C:10]1[C:15]([F:16])=[CH:14][C:13]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[C:12]([CH3:30])[CH:11]=1)#[N:2].S(=O)(=O)(O)[OH:52]>O>[Cl:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:39])[C:32]=1[CH2:31][C:6]1[C:5]2[N:40]=[CH:41][NH:42][C:4]=2[C:3]([C:1]([NH2:2])=[O:52])=[C:8]([NH:9][C:10]2[CH:11]=[C:12]([CH3:30])[C:13]([N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[CH:14][C:15]=2[F:16])[N:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(Nc2nc(Cc3c(Cl)cccc3Cl)c3ncn(COCC[Si](C)(C)C)c3c2C#N)c(F)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O
Product: Cc1cc(Nc2nc(Cc3c(Cl)cccc3Cl)c3nc[nH]c3c2C(N)=O)c(F)cc1N1CCNCC1
Temperature: 90 °C

Procedure:
To the product of Example 51D (190 mg, 0.26 mmol) at 0° C. was added concentrated sulfuric acid (3 mL) and water (0.6 mL) and the mixture was heated at 90° C. for 20 minutes. After quenching with water (20 mL) and adjusting to pH 8 with saturated sodium bicarbonate solvent, the mixture was extracted with 4/1 dichloromethane/methanol (3×100 mL). The organic layers were collected, dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative HPLC using a gradient of 10/90 to 75/25 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 13.63 (s, 1H), 11.98 (s, 1H), 9.63 (s, 1H), 8.64 (m, 3H), 7.90 (d, 1H), 7.83 (s, 1H), 7.56 (d, 2H), 7.39 (t, 1H), 6.90 (d, 1H), 4.74 (s, 2H), 3.25 (m, 4H), 2.95 (m, 4H), 2.07 (s, 3H). MS: 528 (M+H+).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[NH:24][C:23]([CH3:25])=[N:22][N:21]=1.P([O-])([O-])([O-])=O.C([O-])(O)=O.[Na+].C.Cl>CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[NH:24][C:23]([CH3:25])=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: Cc1nnc(S)[nH]1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)[nH]1

Procedure:
7-ACA (13.65 g) and 5-mercapto-2-methyl-1,3,4-triazole (8.15 g) are suspended in 500 ml. of phosphate buffer 0.2 M (Na2HPO4 /NaH2PO4) pH 6.5. To the suspension are added with stirring 10.93 g. of NaHCO3. The reaction medium is heated for 80 minutes with stirring on a 80° C water bath. The solution is then treated with charcoal, cooled (5°-10° C) and acidified to pH 4 with 2 N hydrochloric acid. The obtained suspension is diluted with 150 ml. of acetone and stirred for 30 minutes. The precipitate is filtered, washed with water, acetone and ethyl ether and dried under reduced pressure to yield 7-amino-3-(2-methyl-1,3,4-triazol-5-ylthiomethyl)-3-cephem-4 -carboxylic acid.