Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]1[CH:7]=[CH:8][C:9]2[S:14]C=[CH:12][C:10]=2[CH:11]=1.C(Br)C=C.[NH4+].[Cl-]>C1COCC1>[CH3:4][CH:3]=[CH:2][C:1]1[S:14][C:9]2[CH:8]=[CH:7][CH:6]=[CH:11][C:10]=2[CH:12]=1
Reactant: c1ccc2sccc2c1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: CC=Cc1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
n-Butyl lithium (16.7 ml, 2.5 N in hexanes) was added dropwise to a stirred solution of thianaphthene (5.0 g, 37.3 mmol) in THF (80 mL) at -78° C. under a dry N2 atmosphere. After the addition wascompleted, the mixture was warmed up and stirred at 0° C. for 30 min. Allylbromide (16.1 mL, 186.5 mmol ) was added. After an additional 3.5 h., sat. aq. NH4Cl was added and the reaction mixture was partitioned between water and ether. The ether phase was washed with brine and dried. Silica gel (120 mL) was added. Solvents were removed and the silica adsorbate was flash chromatographed (eluent petroleum ether) to provide the title compound as an oil (3.74 g, 58%): NMR (CDCl3); δ 7.76 (d, J=9 Hz, 1H), 7.66 (d, J=9 Hz, 1H), 7.36-7.20 (m, 2H), 7.02 (s, 1H), 6.14-5.96 (m, 1H), 5.22 (dd, J=2, 17 Hz, 1H), 5.16 (dd, J=2, 17 Hz, 1H), 3.66 (d, J=8 Hz, 2H); MS (EI): [M+] 174 (100%); Anal. Calc. for C11H10S: C, 75.82, H, 5.78, N, 0.00. Found: C, 72.88, H, 5.56, N, 0.13.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:29])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:28].[OH-].[Na+].Cl>C1COCC1.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10](=[O:29])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:28]
Reactant: CCOC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(C(=O)O)on2)ccc1NC(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
Into a 100 ml round bottom flask was added ethyl 3-(4-(3-(2,6-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxylate (1.0 equiv.), NaOH (5.0 equiv.) and 150 ml of 2:1 THF/Water. The mixture was stirred at room temperature for 15 minutes. The reaction mixture was slightly acidified to pH <7 by adding 2N HCl and then the solvent was evaporated. The solid was suspended in water and filtered, given water washings and air-dried. The resulting solid was triturated with minimum quantity of acetone and collected by filtration. This yielded the title compound as a white solid (91%) after it was dried in vacuo; mp 254-258° C. (dec.); 1H NMR (300 MHz; DMSO-d6) δ: 2.31 (s, 3H), 7.10-7.18 (m, 2H), 7.24-7.34 (m, 1H), 7.68-7.72 (m, 2H), 7.78 (s, 1H), 8.03-8.06 (d, J=8.4 Hz, 1H), 8.31 (s, 1H), 8.65 (s, 1H); IR (KBr) 3323, 3189, 3074, 3006, 1743, 1649, 1641, 1569, 1492, 1469, 1243, 1218, 1181, 1003, 833, 733 cm−1.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(-c3cccs3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(-c4cccs4)cc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid ethyl ester (1.3 g, 2.61 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 950 mg (77%); brown solid; mp 235° C.; MS: 471.8 (M+H)+
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[O:12](C1C=C(C=CC=1)N)C1C=CC(N)=CC=1.NC1C=C(C=CC=1)OC1C=CC=C(OC2C=CC=C(N)C=2)C=1.C1C(C(C2C=CC3C(OC(=O)C=3C=2)=O)=O)=CC2C(OC(=O)C=2C=1)=O.C1(=O)OC(=O)C2=CC=CC=C12>CN1CCCC1=O>[CH:8]1[CH:7]=[C:3]([C:4]([NH2:5])=[O:6])[C:2]([C:1]([OH:11])=[O:12])=[CH:10][CH:9]=1
Reactant: Nc1ccc(Oc2cccc(N)c2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: Nc1cccc(Oc2cccc(Oc3cccc(N)c3)c2)c1
Agent: O=C(c1ccc2c(c1)C(=O)OC2=O)c1ccc2c(c1)C(=O)OC2=O
Agent: O=C1OC(=O)c2ccccc21
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The following example illustrates the synthesis of a phthalimide-terminated imide oligomer with theoretical number average molecular weight of 12,000 g/mole. 3,4'-Oxydianiline (3,4'-ODA) (36.00 mmole, 7.2089 g) and 1,3-bis(3-aminophenoxy)benzene (APB) (4.00 mmole, 1.1693 g) were dissolved in N-methylpyrrolidinone (NMP) (~35 mL) in a flask equipped with a mechanical stirrer, condenser and nitrogen inlet. 3,3',4,4'-Benzophenone tetracarboxylic dianhydride (BTDA) (38.38 mmole, 12.3673 g) and phthalic anhydride (PA) (3.240 mmole, 0.4799 g) were added to the solution with enough NMP to total 84.9 g (20% solids). The reaction was stirred at 25° C. for 6 h to form the phthalamide acid-terminated polyamide acid. The inherent viscosity (ηinh) of the phthalamide acid-terminated polyamide acid was 0.43 dL/g in NMP at 25° C. To imidize, toluene (40 mL) was added and the reaction was heated at 160° C. for 24 h. After cooling, a powder precipitated which was washed twice in water and dried ~230° C. in a vacuum to afford a yellow solid in high yield. The resulting phthalimide-terminated polyimide was insoluble in NMP and a glass transition temperature could not be detected while a melting endotherm peaked at 392° C. A film cast from the polyamide acid solution and dried 1 hour each at 100, 225, and 371° C. had a Tg of 252° C., a sharp Tm at 394° C. and was brittle.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[Cl:34][CH:35]([Cl:39])[C:36](Cl)=[O:37]>C(Cl)Cl>[Cl:34][CH:35]([Cl:39])[C:36]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[O:37]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: O=C(Cl)C(Cl)Cl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(Cl)Cl)[C@H]3SC2)s1
Yield: 65.9 %

Procedure:
7-Amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (6.89 g) was suspended in methylene chloride (60 ml) and bis(trimethylsilyl)acetamide (8.12 g) was added to the suspension to give a solution. A solution of dichloroacetyl chloride (3.24 g) in methylene chloride (10 ml) was added to the solution obtained above at -20° C under stirring. The mixture was stirred at the same temperature for 20 minutes and methylene chloride was distilled off from the mixture after addition of a little water. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried. The solvent was distilled off from the solution under reduced pressure. The residue was pulverized by treating with ether and precipitates were collected by filtration and dried to give 7-dichloroacetamido-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (6.0 g).
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].CC([NH:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])=O.O>COCCO>[CH2:2]([S:4][C:13]1[CH:12]=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[C:9]([CH:14]=1)[NH2:8])[CH3:3]
Reactant: CC(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCS
Agent: [Na]
Solvent: O
Solvent: COCCO
Product: CCSc1ccc([N+](=O)[O-])c(N)c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
Sodium (2.76 g.) was added to dry 2-methoxyethanol (75 ml.) and the solution was cooled to 0°-5° C. Ethanethiol (8.72 g.) in 2-methoxyethanol (10 ml.) was added during 5 minutes and the subsequent solution was stirred at 0°-5° C. for 10 minutes and then added in portions to a solution of 5-chloro-2-nitro acetanilide (21.5 g.) in boiling 2-methoxyethanol (150 ml.) during 10 minutes. After 3 hours the mixture was cooled and poured into water (1 l.). The mixture was stirred and cooled to 10° C. The solid which formed was collected by filtration, washed with water, and recrystallized from ethanol to give 5-ethylthio-2-nitroaniline (16.4 g.), m.p. 75°-6° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C@H:12]([CH2:15]OS(C3C=CC(C)=CC=3)(=O)=O)[O:11][C:10]=2[CH:27]=1)(=[O:5])=[O:4].[CH2:30]([NH2:32])[CH3:31].Cl>C(#N)C>[F:1][C:2]([F:29])([F:28])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C@H:12]([CH2:15][NH:32][CH2:30][CH3:31])[O:11][C:10]=2[CH:27]=1)(=[O:4])=[O:5]
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(=O)(=O)C(F)(F)F)cc3O2)cc1
Agent: Cl
Solvent: CC#N
Product: CCNC[C@H]1COc2ccc(S(=O)(=O)C(F)(F)F)cc2O1

Procedure:
Preparation according to Example 2 using [(2R)-7-(trifluoromethylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.27 g, 0.68 mmol), ethanamine (1 ml, 70% in water) and ACN (2 ml). Yield: 0.170 g, 76%. The amine was converted to the hydrochloric acid salt and recrystallized from acetonitrile. M.p. 208° C. MS m/z (rel. intensity, 70 eV) 325 (M+, 1) 58 (bp), 56 (8), 79 (5), 59 (4). [α]=−40° (MeOH).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1.CN(C)C=O>O>[CH:7]([C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:16]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:5]=1)=[O:8]
Reactant: Cc1n[nH]cc1C=O
Reactant: COC(=O)c1cccnc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1-n1cc(C=O)c(C)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
A mixture of 3-methyl-1H-pyrazole-4-carbaldehyde (300 mg, 2.72 mmol), potassium carbonate (565 mg, 4.08 mmol), methyl 2-fluoropyridine-3-carboxylate (507 mg, 3.27 mmol) and dimethylformamide (2 mL) is stirred at 60° C. for 16 h. Water is added and the compound is extracted in ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and solvent is evaporated. The crude mixture is purified by normal phase Isco chromatography using hexane:ethyl acetate, 2:1 as eluent to yield 422 mg of the title compound. MS (m/z): 246 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH:13]1([CH2:16]Br)[CH2:15][CH2:14]1.CI>>[CH:13]1([CH2:16][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:11]=3)[CH2:6][CH2:7][C:8]2=[O:12])[CH2:15][CH2:14]1
Reactant: O=C1CCc2ccc(I)cc2N1
Reactant: BrCC1CC1
Solvent: CI
Product: O=C1CCc2ccc(I)cc2N1CC1CC1

Procedure:
According to the Step 8-1 in synthetic method for EXAMPLE aa8, 3,4-dihydro-7-iodo-2(1H)-quinolinone (1.50 g) and cyclopropylmethyl bromide (0.80 mL) were used instead of a7-1 and MeI to obtain compound aa20-1 (1.23 g) as a pale red amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(C)(C)C.[C:20]1([CH:26]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:29][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(N(CC)CC)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][N:27]([CH:26]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:28][CH2:29]2)=[O:12])=[CH:4][CH:3]=1
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: Cc1ccc(C=CC(=O)O)cn1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C=CC(=O)NCCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cn1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a suspension of 2.71 g of 3-(6-methyl-3-pyridyl)acrylic acid in 70 ml of dry tetrahydrofuran, a solution of 1.68 g of triethylamine in 5 ml of dry tetrahydrofuran is added at room temperature. The resulting solution is cooled to -5° C., and a solution of 2.0 g of pivaloyl chloride in 5 ml of dry tetrahydrofuran is added slowly. The mixture is stirred at the same temperature for 0.5 hour and cooled to -10° C., and a solution of 6.43 g of 4-(4-diphenylmethyl-1-piperazinyl)butylamine in 5 ml of dry tetrahydrofuran is added slowly. The mixture is stirred for 0.5 hour at between -10° C. and -5° C. and then at room temperature overnight. To the reaction mixture is added 50 ml of 10% aqueous potassium carbonate, and the resulting mixture is extracted with three 100-ml portions of ethyl acetate. The combined extracts are washed with water and dried over magnesium sulfate, and the solvent is distilled off. The residue is recrystallized from acetonitrile to give 5.63 g of the title compound, m.p. 129°-131° C.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:42])/[CH:27]=[CH:28]/[C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.CSC>[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:42])[CH2:27][C@H:28]([C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)c1cccc(/C=C/C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c1
Reactant: Brc1ccccn1
Agent: CC(C)[Mg]Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc([C@@H](CC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccccn2)c1
Reaction time: 1.5 h
Yield: 37 %

Procedure:
To a 1.0 M solution of isopropylmagnesium chloride (1.0 mL, 2.08 mmol) in THF was added 2-bromopyridine (0.198 mL, 2.08 mmol) and the mixture was stirred for 1.5 hours. This dark solution, at 0° C., was quickly added to a cooled (−40° C.) solution of CuBr.DMS complex (0.206 g, 1.01 mmol) in THF (2 mL) and dimethylsulfide (1 mL), and the resulting mixture was stirred at −40° C. for 10 min, then placed in an ice bath. Tert-butyl 3-{(1E)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxoprop-1-enyl}benzoate from the previous step, dissolved in THF (2 mL), was added dropwise and the mixture was stirred for 1.5 hours. The reaction was quenched with 20% aqueous NH4Cl solution, the dimethylsulfide was removed under reduced pressure and the mixture was partitioned between EtOAc and H2O. The layers were separated, the water layer was extracted with EtOAc, and the combined organics were washed with H2O and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed on a 10 g ISCO column using 0-40% EtOAc/hexanes over 40 min. The lower diastereomer was combined to give tert-butyl 3-{(1R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxo-1-pyridin-2-ylpropyl}benzoate as an oil (0.12 g, 37%). Absolute chirality was assigned based on literature precedent. TLC Rf=0.3 (1:1 EtOAc:hexanes, UV visualization); HPLC RT=2.1 min, method B; M+H=488.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]2[CH2:15][CH2:16][NH:17][CH2:18][C:7]1=2.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32].C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:29][CH2:30][C:31]([N:17]1[CH2:16][CH2:15][C:8]2[C:9]3[C:10]([N:6]([CH2:5][C:4]4[CH:19]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=4)[C:7]=2[CH2:18]1)=[N:11][CH:12]=[CH:13][CH:14]=3)=[O:32]
Reactant: Fc1cccc(Cn2c3c(c4cccnc42)CCNC3)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)N1CCc2c(n(Cc3cccc(F)c3)c3ncccc23)C1
Reaction time: 0.5 h

Procedure:
To a suspension of 9-(3-fluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine (500 mg) produced by operation in accordance with Reference manufacturing example 1 in THF (10 mL) were sequentially added triethylamine (0.59 mL) and chloroacetyl chloride (0.135 mL), and the mixture was stirred for 30 minutes. The reaction mixture was poured into an aqueous saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (459 mg) having the following physical property values.
Reaction SMILES: Cl.[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH2:26])[C@H:22]3[S:21][CH2:20][C:19]=2[CH2:28][S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[S:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39][C:40]([NH:42][C:43]1[S:44][CH:45]=[C:46](/[C:48](=[N:52]/[O:53][C:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)/[C:49](O)=[O:50])[N:47]=1)=[O:41])([CH3:38])([CH3:37])[CH3:36].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O>ClCCl.Cl>[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH:26][C:49](=[O:50])/[C:48](/[C:46]4[N:47]=[C:43]([NH:42][C:40]([O:39][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:41])[S:44][CH:45]=4)=[N:52]\[O:53][C:54]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)[C@H:22]3[S:21][CH2:20][C:19]=2[CH2:28][S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[S:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CSc3c[nH]nn3)CS[C@H]12
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4c[nH]nn4)CS[C@H]23)cs1
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a suspension of 7β-amino-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (110 mg: 0.2 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (122 mg: 0.23 mMol.) in dichloromethane (3 ml) are added N-methylmorpholine (72 μl: 0.66 mMol.) and phenyl dichlorophosphate (33 μl: 0.22 mMol.) at -30° C. After stirring for 2 hours, the reaction mixture is diluted with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried, purified by silica gel chromatography, and crystallized from toluene to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (110 mg). m.p. 190°-200° C. (decomp.).
Reaction SMILES: [CH:1]1([CH:4]=[O:5])[CH2:3][CH2:2]1.[Si:6]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Mg]Br)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([CH:4]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][O:13][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8])[OH:5])[CH2:3][CH2:2]1
Reactant: O=CC1CC1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1C(O)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Magnesium (2.20 g) was suspended in tetrahydrofuran (4 ml) and iodine (2 mg) was added. Thereto was added dropwise a solution of 2-bromo-1-(tert-butyldimethylsilyloxymethyl)benzene (24.0 g) obtained in Step 1 in tetrahydrofuran (10 ml) over 30 min and the reaction mixture was heated under reflux for 1 hr. Thereto was added tetrahydrofuran to give 1M 2-(tert-butyldimethylsilyloxymethyl)phenylmagnesium bromide-tetrahydrofuran solution. Then cyclopropanecarboxaldehyde (2.80 g) was dissolved in tetrahydrofuran (120 ml), and 1M 2 -(tert-butyldimethylsilyloxymethyl)phenylmagnesium bromide—tetrahydrofuran solution (80 ml) was added dropwise under ice-cooling over 50 min. The reaction mixture was stirred at room temperature for 12 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution (8 ml) under ice-cooling and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5) to give the title compound (8.20 g).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([O:8][CH3:7])=[O:18])=[CH:11][CH:12]=1)=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
To a slurry of methyltriphenylphosphonium bromide (10.88 g, 30.46 mmol, 1 eq.) and potassium tert-butoxide (31 mL, 1 M solution in THF, 30.46 mmol, 1 eq.) in THF is added methyl-4-formylbenzoate (5.0 g, 30.46 mmol, 1 eq.). The bright yellow reaction mixture is stirred at room temperature for 5 hrs. Hexane is added and after stirring for 10 minutes, the mixture is filtered and washed twice with hexanes. Solvent is removed in vacuum and the crude oily residue is purified by silica gel chromatography (0-14% ethyl acetate/hexanes) to give 3.76 g of a white oily solid, methyl 4-vinylbenzoate (23.21 mmol, 76.2% yield). 1H NMR (300 MHz, CDCl3): δ 7.99 (2H, d, J=9 Hz), 7.45 (2H, d, J=9 Hz), 6.76 (1H, dd, J=17, 11 Hz), 5.86 (1H, d, J=17 Hz), 5.37 (1H, d, J=11 Hz), 3.91 (3H, s).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:6](=[O:22])[N:7]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])[CH:8]=1)#[N:2].N.[OH:32]O.O>CO>[CH:15]1([NH:14][C:12]([C:11]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:9]([N:7]3[C:6](=[O:22])[C:5]([NH:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[N:4][C:3]([C:1]([NH2:2])=[O:32])=[CH:8]3)[CH:10]=2)=[O:13])[CH2:16][CH2:17]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C#N)nc(NCc2ccccc2)c1=O
Reactant: OO
Agent: N
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C(N)=O)nc(NCc2ccccc2)c1=O
Reaction time: 12 h

Procedure:
To a stirred solution of 3-[5-cyano-2-oxo-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 104, 100 mg) in methanol (1 mL) was added conc. ammonia solution (1 mL) followed by 30% hydrogen peroxide solution (1 mL). After 12 h, water was added and the mixture was extracted with dichloromethane. The pooled organics were washed with brine, dried (MgSO4), filtered and the solvent removed. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound (31 mg).