Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[N:31]1([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][C@H:32]1[C:41](O)=[O:42].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH2:22][C@@H:2]([NH:1][C:41]([C@@H:32]2[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:40][N:31]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:42])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from (2R)-2-amino-3-(3,4-dichlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}-piperazinyl)propan-1-one (Step 2) (350 mg, 0.750 mmol) according to the procedure for Preparation XIX using Boc-L-Tic-OH (220 mg, 0.78 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (450 mg, 1.5 mmol), HOAT (100 mg, 0.764 mmol), and DMF (5 mL) (590 mg crude). MS (ESI, pos. ion) m/z: 730 (M+H), (ESI, neg. ion) m/z: 728 (M−H). Calc'd for C35H41Cl2N5O6S: 729.22.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([OH:22])=[O:21]>O1CCCC1>[CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([O-:22])=[O:21]
Reactant: O=CO
Agent: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Solvent: C1CCOC1
Product: O=C[O-]
Temperature: 50 °C

Procedure:
To a stirred solution of O-desmethylvenlafaxine (13.17 g, 0.050 mol.) in tetrahydrofuran (300 mL) at 62–65° C., under a nitrogen atmosphere, was added 96 wt % formic acid (2.20 mL, d=1.22, 0.056 mol., 1.2 molar excess) in tetrahydrofuran (30 mL) dropwise over a period of 2 minutes, while maintaining the temperature in the range 62° C.–64° C. The solution was filtered through a pad of Celite filter aid (prewashed with tetrahydrofuran) and the filter pad was washed with hot (60–65° C.) tetrahydrofuran (2×20 mL). The filtrate and washings (temperature ˜35° C.) were warmed to 50° C. under a nitrogen atmosphere and allowed to cool. At 48° C. the stirred solution was seeded with crystals of O-desmethylvenlafaxine formate. Crystallization ensued immediately. When the slurry of crystals had cooled to 22° C. it was chilled to −5° C. to −10° C. The crystals were collected on a filter and washed with chilled (−5 to −10° C.) tetrahydrofuran (2×30 mL). After drying in a vacuum oven at room temperature under oil pump vacuum for 23 hours the product, O-desmethylvenlafaxine formate, weighed 13.79 g, (89% yield) and it had mp=149 150° C. It was characterized by DSC (sharp endotherm at 151.5° C.).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[F:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(OCc4cccc(F)c4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (53 mg, 0.30 mmol) was reacted with 4-[2-amino-4-(3-fluoro-benzyloxy)-phenylsulfanyl]-phenol (102 mg, 0.30 mmol) for 20 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (60 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.76 (s, 3H) 5.16 (s, 2H) 6.27 (d, J=6.99 Hz, 1H) 6.64 (d, J=8.46 Hz, 2H) 7.03-7.36 (m, 7H) 7.45 (m, J=6.26 Hz, 1H) 7.80 (d, J=8.82 Hz, 1H) 8.39 (d, J=6.98 Hz, 1H) 8.99 (d, J=8.82 Hz, 1H) 9.78 (s, 1H) 11.02 (br s, 1H) 14.39 (br s, 1H); MS (ESI+) m/z, 484 (M+H−TFA)+; (ESI−) m/z, 482 (M−H−TFA)−.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7](F)=[CH:6][C:5]=1[Br:14].O[S:17](O)(=O)=O.[N+]([O-])(O)=O.C[O:26][C:27](=O)[C:28]1C=CC(F)=CC=1Br.[OH-].[Na+]>CCOC(C)=O>[Br:14][C:5]1[C:4]([C:3]([OH:2])=[O:15])=[CH:9][C:8]2[NH:10][C:27](=[O:26])[CH2:28][S:17][C:7]=2[CH:6]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1Br
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1ccc(F)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CCOC(C)=O
Product: O=C1CSc2cc(Br)c(C(=O)O)cc2N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43 %

Procedure:
2-Bromo-4-fluoro-5-nitro-benzoic acid methyl ester. To conc. fuming H2SO4 (8 mL) at 0° C. was added conc. fuming HNO3 (8 mL) and the mixture allowed to stand for 5 min. To a solution of 2-bromo-4-fluoro-benzoic acid methyl ester (9.32 g, 40 mmol) at 0° C., the mixture of acids was added dropwise over 30 min. The mixture was allowed to warm to RT and was stirred for 18 h. The mixture was poured into ice water, diluted with EtOAc, and treated with 6 N NaOH. The aqueous layer was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO4), and concentrated. The crude material was purified on SiO2 (0-25% EtOAc/hexanes) to provide 4.9 g (43%) of the title compound. 1H NMR (500 MHz, CDCl3): 8.61 (d, J=8.0, 1H), 7.66 (d, J=10.0, 1H), 3.91 (s, 3H).
Reaction SMILES: II.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([SH:15])[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[O:16][CH3:17].S(=O)(O)[O-].[Na+]>C(O)C>[OH:3][C:4]1[C:5]([O:16][CH3:17])=[CH:6][C:7]2[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[S:15][C:8]=2[CH:9]=1
Reactant: COc1cc(C=C(S)C(=O)O)ccc1O
Agent: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc2cc(C(=O)O)sc2cc1O

Procedure:
Iodine (90 g) was added to a stirred mixture of the product from Step B (73 g) and 90% ethanol (2000 mL). The resultant dark mixture was heated at reflux for 24 hours. Saturated sodium bisulfite solution (20 mL) was added to the cooled reaction mixture and the ethanol was removed in vacuo. The aqueous residue was diluted to 1500 ml with water and extracted with ethyl acetate (4×400 mL). The combined extracts were evaporated in vacuo and the residue was heated on the steam bath with 1N sodium hydroxide solution (1500 mL) for 3 hours. The solution was treated with charcoal, filtered, diluted to 2500 mL with water and acidified with concentrated hydrochloric acid. The precipitated solid was collected, washed with water and dried; yield 36.8 g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:14][NH2:15].[N:16]1([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:14][N:15]1[C:4](=[O:6])[C:3]2[C:2](=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][CH:7]=2)[N:1]=[C:29]1[C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH2:24][CH2:23][CH2:22][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:27]=1
Reactant: O=Cc1cccc(OCCCN2CCCCC2)c1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: CN
Product: Cn1c(-c2cccc(OCCCN3CCCCC3)c2)nc2cc([N+](=O)[O-])ccc2c1=O

Procedure:
The entitled compound was obtained according to the method of Example 70 but starting from 2-amino-4-nitrobenzoic acid, methylamine and 3-(3-piperidin-1-ylpropoxy)benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[C:14]3Cl)=[CH:4][N:3]=1.[C:22]1([CH:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CS(C)=O>[Cl:1][C:2]1[C:7]([N:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[C:14]3[N:33]2[CH2:34][CH2:35][N:30]([CH:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:29])[CH2:31][CH2:32]2)=[CH:4][N:3]=1
Reactant: CN(C)c1cc(-c2ccc3nccc(Cl)c3c2)cnc1Cl
Reactant: CC(c1ccccc1)N1CCNCC1
Solvent: CS(C)=O
Product: CC(c1ccccc1)N1CCN(c2ccnc3ccc(-c4cnc(Cl)c(N(C)C)c4)cc23)CC1
Temperature: 110 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
(Some starting materials may be obtained from Chess GmbH, Mannnheim, Germany) To a microwave vial (5 mL), 2-chloro-5-(4-chloroquinolin-6-yl)-N,N-dimethylpyridin-3-amine (0.0846 g, 0.266 mmol) and 1-(1-phenylethyl)-piperazine (0.125 mL, 0.665 mmol) were added into DMSO (4 mL). The mixture was stirred at 90 oC for 2.5 h, at 110° C. for 3 h, then at RT for overnight. The reaction was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were washed with saturated aqueous NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (eluent: acetone in hexanes 0% -50%) to afford the title compound as a white solid (0.0886 g). m/z: calc'd for C28H30ClN5; 471.2, found: 472.2 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.46 (d, J=6.6 Hz, 3 H), 2.63-2.89 (m, 4 H), 2.94 (s, 6 H), 3.29 (t, J=4.4 Hz, 4 H), 3.51 (d, J=6.7 Hz, 1 H), 6.88 (d, J=5.0 Hz, 1 H), 7.28-7.42 (m, 5 H), 7.56 (d, J=2.2 Hz, 1 H), 7.84 (dd, J=8.7, 2.1 Hz, 1 H), 8.10-8.20 (m, 2 H), 8.33 (d, J=2.2 Hz, 1 H), 8.75 (d, J=5.0 Hz, 1 H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[CH2:8][NH:9][CH2:10][C:3]=12.[Cl:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:15][NH:16][C:17]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]=[C:19](S(C)=O)[N:18]=1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:15][NH:16][C:17]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]=[C:19]([N:9]2[CH2:8][C:4]3[C:3](=[N:2][CH:7]=[CH:6][CH:5]=3)[CH2:10]2)[N:18]=1
Reactant: c1cnc2c(c1)CNC2
Reactant: CCOC(=O)c1cnc(S(C)=O)nc1NCc1ccc(OC)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N2Cc3cccnc3C2)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride salt (1.86 g, 12 mmol) was added into the solution of ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-methanesulfinyl-5-pyrimidine carboxylate in DCM. The mixture was cooled in an ice bath, and triethylamine was added dropwisely (2.5 mL, 17.9 mmol). The reaction mixture was stirred at ambient temperature overnight. LC-MS was used to monitor the reaction. After the completion of the reaction, water (30 mL) was added for precipitation. The solid was filtrated and dried to give ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-(5H-pyrrolo[3,4-b]pyridine-6(7H)yl)-5-pyrimidine carboxylate (3.0 g, 65.6% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([CH:12]2[N:16]3[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:15]3[C@@H:14]([CH3:23])[C:13]2=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:51][C@@H:52]1[CH2:56][CH2:55][NH:54][C:53]1=[S:57]>C(#N)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:16]3[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:15]3[C@@H:14]([CH3:23])[C:13]=2[S:51][C@@H:52]2[CH2:56][CH2:55][NH:54][C:53]2=[S:57])=[O:11])=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: S=C1NCC[C@H]1S
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@@H]3CCNC3=S)[C@H](C)[C@H]12
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
(1R, 5R, 6S)-6-[(1R)-1-Hydroxyethyl]-1-methyl-2-oxocarbapenam-3-carboxylic acid 4-nitrobenzyl ester (8.3 g) is dissolved in anhydrous acetonitrile (50 ml), and thereto are added dropwise diisopropylethylamine (4 ml) and diphenylphosphoryl chloride (4.8 ml) in this order under nitrogen gas below 0° C. After stirring the mixture at the same temperature for 30 minutes, a solution of (3R)-3-mercaptopyrrolidine-2-thione (4 g) and diisopropylethylamine (4 ml) in anhydrous acetonitrile (50 ml) is added dropwise to the reaction mixture below -15° C. The mixture is stirred at the same temperature for 1.5 hour, and water (50 ml) is added to the reaction mixture. The mixture is concentrated under reduced pressure to remove acetonitrile. The residue is extracted with ethyl acetate, and the extract is washed with water, dried and evaporated to dryness under reduced pressure. The residue is purified by silica gel column chromatography (eluent, chloroform:methanol=99:1) to give (1R, 5S, 6S)-2-[(3R)-pyrrolidine-2-thion-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (4.3 g) as an amorphous powder.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[C:15](=[N:22][O:23][CH3:24])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1.[OH-].[Na+:28]>O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O-:10])=[O:9])[N:5]2[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[C:15](=[N:22][O:23][CH3:24])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1.[Na+:28]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1
Agent: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(=N)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CC(C)S[C@H]12)c1csc(N)n1

Procedure:
To a suspension of 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (4.8 g.) in water (48 ml.) was added dropwise 1N aqueous sodium hydroxide solution at the rate that the pH value of the mixture was not more than 7. The mixture was filtered and then lyophilized to give sodium 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as sodium 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (4.8 g.), mp>250° C. This compound is suspended in dried dimethylformamide (20 ml.), and to the suspension was added iodomethyl pivalate (2.30 g.) with vigorous stirring under cooling to 3° to 5° C., and then the mixture was stirred for 20 minutes at the same temperature. The reaction mixture was poured into a mixture of ethyl acetate (60 ml.) and ice-water (10 ml.), and the mixture was well shaken. The ethyl acetate layer was separated, washed with a saturated aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution in turn. After the ethyl acetate layer was dried over magnesium sulfate, ethyl acetate was distilled off under reduced pressure. The residual oil was pulverized in diethyl ether (25 ml.), collected by filtration and then dried to give pivaloyloxymethyl 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as pivaloyloxymethyl 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (1.44 g.), mp 165° to 170° C. (dec.).
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:24])([F:23])[C:9]1[C:10]([S:15]([NH:18][C:19](=[O:22])OC)(=[O:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[CH3:25][C:26]1[CH2:30][CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:28][N:27]=1>N1C=CC=CC=1>[F:23][C:8]([F:7])([F:24])[C:9]1[C:10]([S:15]([NH:18][C:19]([N:28]2[CH:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:30][C:26]([CH3:25])=[N:27]2)=[O:22])(=[O:16])=[O:17])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC1=NNC(c2ccccc2)C1
Reactant: COC(=O)NS(=O)(=O)c1ncccc1C(F)(F)F
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC1=NN(C(=O)NS(=O)(=O)c2ncccc2C(F)(F)F)C(c2ccccc2)C1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A dry dioxane (10 ml) solution containing methyl N-(3-trifluoromethylpyridine-2-sulfonyl)carbamate (0.43 g, 1.5 mmol), 3-methyl-5-phenyl-2-pyrazoline (0.48 g, 3.0 mmol) and pyridine (0.45 g) gas refluxed under heating and stirring for one hour. After cooling the mixture, the solvent was distilled off under reduced pressure, and the residue was stirred together with ethyl ether. Precipitated crystals were collected by filtration and then thoroughly washed with ethyl ether, and the crystals were suspended in 20 ml of water. Then, the pH was adjusted to a level of from 1 to 2 with concentrated hydrochloric acid, and the suspension was stirred at room temperature for 5 minutes. Crystals were collected by filtration, thoroughly washed with water and then with ethyl ether and dried to obtain 0.51 g of desired 1-(3-trifluoromethylpyridine-2-sulfonylcarbamoyl)-3-methyl-5-phenyl-2-pyrazoline. Melting point: 185°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:6]([N:18]([CH3:31])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[C:6]([NH:18][CH3:31])[CH:5]=1
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N(C)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1cc(C(=O)OC)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After dissolving 4-tert-butoxycarbonylamino-3-[methyl-(2-nitro-benzenesulfonyl)-amino]-benzoic acid methyl ester (1.41 g, 2.73 mmol) in dimethylformamide (10 ml), potassium carbonate (1.13 g, 8.16 mmol) and thiophenol (0.307 ml, 2.99 mmol) were added in an ice bath, and the mixture was stirred at room temperature for 1 hour. Water (100 ml) was added to the reaction mixture, and extraction was performed with ethyl acetate (40 ml×3 times). The obtained organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (n-hexane/ethyl acetate=85/15) to obtain 4-tert-butoxycarbonylamino-3-methylamino-benzoic acid methyl ester. The compound was identified by LC-MS. Yield: 794.3 mg (62.7%), [M+1]=281.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][S:14][C:15]1[NH:16][C:17]2[CH:23]=[C:22]([CH3:24])[C:21]([CH3:25])=[CH:20][C:18]=2[N:19]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][S:14][C:15]1[N:16]([C:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:41])[C:17]2[CH:23]=[C:22]([CH3:24])[C:21]([CH3:25])=[CH:20][C:18]=2[N:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc2nc(SCc3ccccc3C(=O)OC(C)(C)C)[nH]c2cc1C
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc2nc(SCc3ccccc3C(=O)OC(C)(C)C)n(C(=O)c3ccccc3)c2cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-((5,6-dimethylbenzimidazole-2-ylthio)methyl)benzoic acid t-butyl ester (30 mg, 0.082 mmol) was dissolved in 3 ml of chloroform, to which triethylamine (17 μl, 0.123 mmol) and benzoyl chloride (14 μl, 0.123 mmol) were sequentially added and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added, followed by extraction with ethyl acetate. After drying the ethyl acetate phase with anhydrous sodium sulfate, it was concentrated, and 2-((5,6-dimethyl-1-(phenylcarbonyl)benzimidazole-2-ylthio)methyl)benzoic acid t-butyl ester was obtained (38 mg, yield quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[CH2:11][OH:12].CO>C1C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[CH:11]=[O:12]
Reactant: COc1cc(Cl)c(CO)c(Cl)c1
Agent: O=[Mn]=O
Solvent: CO
Solvent: c1ccccc1
Product: COc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 25 °C

Procedure:
A suspension of (2,6-dichloro-4-methoxy-phenyl)-methanol (5.69 g, 27.49 mmol) and MnO2 (15 g) in benzene (100 mL) was stirred at reflux, utilizing a Dean-Stark trap, overnight. The suspension was cooled to room temperature, filtered through Celite, and the solvent was removed by evaporation to yield 4.69 g (83%) of crude white solid. An analytical sample was obtained by recrystallization from methanol to yield white needle crystals: mp 104-106° C.; 1H NMR (DMSO-d6): δ 3.90 (3H, s), 7.21 (2H, s), 10.29 (1H, s); MS (EI) m/z 204/206/218 (M+−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:32])[CH:24]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1
Yield: 83.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), m-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.057 g (83%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]([Cl:16])([CH3:15])[CH:13]=O.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:13]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]([Cl:16])([Cl:11])[CH3:15])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: CC(Cl)(Cl)C=O
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(Cl)(Cl)C(NC(=O)c1ccc(F)cc1)n1nnc2ccccc21

Procedure:
A suspension of 4-fluorobenzamide, 2,2-dichloropropionaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 53A to provide the desired product.