Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH:9]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:2].C[Si](C)(C)[O:32][CH2:33][CH2:34]O[Si](C)(C)C.C[Si](Cl)(C)C>C(O)CO>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH:9]([CH:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:10]32[O:32][CH2:33][CH2:34][O:14]3)[CH2:7]1)=[O:5])[CH3:29]
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Reactant: CCN(CC)C(=O)C1CN2CCC1C(=O)C2C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: OCCO
Product: CCN(CC)C(=O)C1CN2CCC1C1(OCCO1)C2C(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 88.5 %

Procedure:
A mixture of (3R*, 4R*)-N,N-diethyl-6-diphenylmethyl-5-oxo-1-azabicyclo[2.2.2]octane-3-carboxamide (10 g, 26 mmol), 1,2-bis(trimethylsiloxy)ethane (6 g, 29 mmol), trimethylsilyl chloride (20 ml) and ethylene glycol (50 ml) was heated at 100° C. for 3 hours. After by-products were removed by distillation 93° C./atmosphere pressure), the mixture was poured into cold aqueous sodium bicarbonate (NaHCO3) (250 ml) and extracted with methylene chloride (CH2Cl2) (100 ml) three times. The combined extracts were dried over sodium sulfate (Na2SO4) and concentrated. The clude was purified by recrystallization from ethyl acetate (EtOAc)/hexane to give 21 (1:2 mixture at 6-position; 23 mmol, 88%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])(C)(C)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:16]=1[S:23]([NH2:26])(=[O:25])=[O:24]>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:6]2[CH:5]=[CH:4][C:3]([F:8])=[CH:2][CH:7]=2)[OH:22])=[CH:17][C:16]=1[S:23]([NH2:26])(=[O:25])=[O:24]
Reactant: Fc1ccccc1Br
Reactant: NS(=O)(=O)c1cc(C=O)ccc1Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(C(O)c2ccc(F)cc2)ccc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 18.5 %

Procedure:
A solution of 590 mg of 1-bromofluorobenzene (1.11 mmol, 3 equivalent) in 10 mL of anhydrous tetrahydrofuran is stirred at −78° C. as 3.9 mL of tert-butyllithium (1.7 M in cyclohexane, 6.66 mmol, 6 equivalent) is added drop-wise. The reaction mixture is stirred at −78° C. for 2 h, then is transfered to a previously prepared a solution of 243 mg of 2 chloro-5-formyl-benzenesulfonamide (1.11 mmol, 1 equivalent) and 0.65 mL of tert-butyllithium (1.7 M in cyclohexane, 1 equivalent) in 10 mL of anhydrous tetrahydrofuran. The reaction is allowed to warm to room temperature and stirred at room temperature for 18 h. The reaction is quenched with 0.1 N HCl and then extracted several times with ethyl acetate. The combined organic extracts are dried over sodium sulfate, and concentrated in vacuo to give 65 mg of the title compound which is carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[C:32]4[C:27]([CH:28]=[CH:29][C:30]([C:34]([O:36]C)=[O:35])=[CH:31]4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1.CO.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[C:32]4[C:27]([CH:28]=[CH:29][C:30]([C:34]([OH:36])=[O:35])=[CH:31]4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1
Reactant: COC(=O)c1ccc2ccc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3ccc(C(=O)O)cc3c2)cc1
Temperature: 100 °C
Yield: 85.6 %

Procedure:
A solution of methyl 7-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-naphthalenecarboxylate (0.057 g, 0.1 mmol) in tetrahydrofuran (1.0 mL) was placed in a microwave reaction tube. Methanol (0.5 mL) was added followed by 1 N sodium hydroxide (0.15 mL, 0.15 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 600 seconds. The solution was neutralized and concentrated. Water was added and the mixture was filtered. The resulting solid was dried in a vacuum oven at 45° C. with P2O5 to yield the title compound (0.048 g, 76% as 0.20 tetrahydrofuran) 1H NMR (DMSO-d6) δ 13.4-12.8 (broad s, approximately 1H), 8.59 (s, 1H), 8.31 (s, 1H), 8.01 (d, J=9 Hz, 1H) 7.94-7.90 (m, 3H), 7.79 (d, J=8 Hz, 2H), 7.43 (d, J=8 Hz, 2H), 7.28-7.24 (m, 1H), 7.14 (d, J=8 Hz, 2H), 4.98 (s, 2H), 3.39-3.21 (2m, overlapping H2O, total 3H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H). HRMS C32H27NO4Cl2 m/z 560.1395 (M+H)+Cal; 560.1409 (M+H)+Obs.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:19]([CH3:20])=[N:9][C:3]=2[CH:4]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Product: Cc1nc2cc(F)ccc2n1-c1ccccc1
Yield: 61 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 1-Bromo-4-fluoro-2-nitrobenzene and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as brown solid (69 mg, 61%). 1H NMR (DMSO) δ 2.49 (s, 3 H), 7.17-7.32 (m, 2 H), 7.61-7.73 (m, 6 H).
Reaction SMILES: N[C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[BrH:12].BrBr.N([O-])=O.[Na+]>O>[Br:12][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Br
Reactant: COC(=O)c1nccnc1N
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1nccnc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a solution of methyl 3-amino-2-pyrazinecarboxylate (13.06 mmol, 2 g) in hydrobromic acid (13.06 mmol, 7.4 ml, 1.057 g) at 0° C. was added bromine (38.9 mmol, 2 mL, 6.22 g) drop wise and then a solution of sodium nitrite (33.3 mmol, 2.3 g) in water (4 mL). The reaction was stirred for 2 h at 0° C. and the reaction mixture was extracted with CH2Cl2. Organic layer was dried and evaporated to give crude methyl 3-bromopyrazine-2-carboxylate 101 (1.2 gr, 43%). (m/z)=217 and 219 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[ClH:11].[Cl:12][CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([S:21][CH2:22][CH2:23][CH2:24][Cl:25])[CH:17]=[CH:16][N:15]=1>>[ClH:12].[ClH:11].[Cl:25][CH2:24][CH2:23][CH2:22][S:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:13][S:1][C:2]2[NH:3][C:4]3[C:5]([N:10]=2)=[N:6][CH:7]=[CH:8][CH:9]=3)[C:19]=1[CH3:20]
Reactant: Sc1nc2ncccc2[nH]1
Reactant: Cc1c(SCCCCl)ccnc1CCl
Agent: Cl
Product: Cc1c(SCCCCl)ccnc1CSc1nc2ncccc2[nH]1
Yield: 88 %

Procedure:
According to the procedure described in Example C1., the reaction of 2-mercapto-1H-imidazo[4,5-b]pyridine with 2-chloromethyl-4-(3-chloropropylthio)-3-methylpyridine hydrochloride gives the title compound as a colorless powder; m.p. 186-188° C.; yield: 88% of theory.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=[CH:8][S:9](Cl)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[CH:22]=[C:21]1[CH2:29][N:30]1[CH2:34][CH2:33][C@H:32]([NH2:35])[C:31]1=[O:36])=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[CH:22]=[C:21]1[CH2:29][N:30]1[CH2:34][CH2:33][C@H:32]([NH:35][S:9]([CH:8]=[CH:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:11])=[O:10])[C:31]1=[O:36])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)n1c(CN2CC[C@H](N)C2=O)cc2cnccc21
Product: CC(C)(C)OC(=O)n1c(CN2CC[C@H](NS(=O)(=O)C=Cc3ccc(Cl)s3)C2=O)cc2cnccc21

Procedure:
The title compound is prepared as described in EXAMPLE 56, Part A using 2-(5-chlorothiophen-2-yl)-ethenesulfonyl chloride and 2-[3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester as starting material. The crude product can be purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound as a white solid or used in the subsequent step after an aqueous work-up without further purification.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].[C:20]([N:27]1[CH2:32][CH2:31][CH:30](Br)[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(OCC)(=O)C>CN(C=O)C>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[CH2:8][O:9][C:10]=2[C:2]=1[O:1][CH:30]1[CH2:31][CH2:32][N:27]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:28][CH2:29]1
Reactant: COc1ccc2c(c1O)OCC2=O
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1OC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 80 °C
Reaction time: 12 h
Yield: 3.1 %

Procedure:
A solution of 7-hydroxy-6-methoxybenzofuran-3(2H)-one (0.30 g, 1.7 mmol) in DMF (5.0 mL) was added with potassium carbonate (1.0 g, 7.2 mmol), and N-Boc-4-bromopiperidine (0.50 g, 1.9 mmol), and the mixture was stirred at 80° C. for 12 hours. The reaction mixture was added with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (1:1)) to obtain tert-butyl 4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yloxy)piperidine-1-carboxylate (0.019 g, 3%).
Reaction SMILES: CN(C)[CH:3]=[O:4].C1([C@@H](N)C)C=CC=CC=1.[CH2:15]([O:22][C@@H:23]([CH3:27])[C:24](O)=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S(Cl)(Cl)=O>CO>[CH2:15]([O:22][C@@H:23]([CH3:27])[C:24]([O:4][CH3:3])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: C[C@H](OCc1ccccc1)C(=O)O
Agent: C[C@H](N)c1ccccc1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](C)OCc1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Dimethyl formamide (0.5 ml) was added to a mixture of (S)-1-phenylethanamine salt of (S)-2-(benzyloxy)propanoic acid compound of formula-13a obtained in step-c) of above examples-9 &. 10 (200 g) and methanol (600 ml) and the reaction mixture was cooled to 0-5° C. Thionyl chloride (58.4 ml) was slowly added to the reaction mixture at 0-5° C. over a period of 1 hour and stirred for 1 hour at 0-10° C. After completion of the reaction, the reaction mixture was quenched with water and extracted with dichloro methane. Both aqueous and dichloro methane layers were separated, dichloro methane layer was washed with 10% sodium chloride and water. Distilled off the solvent completely from dichloro methane layer to get title compound. Yield: 129 g; Chiral purity: 99.5%
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([C:12](=O)[CH2:13]Br)[CH:9]=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[C:22]([NH2:24])=[S:23])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C:22]2[S:23][CH:13]=[C:12]([C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)[N:11]=3)[N:24]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[CH3:17]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: O=C(CBr)c1cccc(-n2cncn2)n1
Product: CCOc1ccc(-c2nc(-c3cccc(-n4cncn4)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(1,2,4-triazol-1-yl)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(1,2,4-triazol-1-yl)-2-pyridyl]thiazole.
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[C:13](=[O:14])[NH:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[O:9][C:8]=3[S:19][C:5]=2[CH2:4][CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH:1]1[C:6]2[C:7]3[C:13](=[O:14])[NH:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[O:9][C:8]=3[S:19][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccccc2Oc2sc3c(c21)CCCC3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: O=C1Nc2ccccc2Oc2sc3ccccc3c21
Yield: 84.6 %

Procedure:
1,2,3,4-Tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one (1.5 g) and dichlorodicyano-p-benzoquinone (2.6 g) was dissolved in benzene (45 ml) and the mixture was stirred under reflux with heating for 12 hours. The reaction mixture was evaporated under reduced pressure to remove the solvent, and the residue was added to a mixture of chloroform/water. The organic layer was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to give [1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one (1.25 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH:30][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Reactant: NCc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(NCc3ccccc3)c(Br)c2)c(SC)s1
Temperature: 50 °C

Procedure:
To a vial containing a stirbar was added 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.020 g, 0.045 mmol), (Example 2: step c), benzylamine (0.005 g, 0.407 mmol), MeOH [2.0 mL]. Reaction vessel was sealed and heated to 50° C. for 72 hours. Removal of the solvents in vacuo followed by chromatography of the residue (10%–20% EtOAc/Hx) yielded the title compound. ESI-MS (m/z): Calcd. for C19H17BrN2O4S3: 514.45 (M+H); found 513.2, 515.1.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[CH2:7][NH:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.[Cl:12][CH2:13][C:14](Cl)=[O:15].C.C(OC)(C)(C)C>C1C=CC=CC=1>[Cl:12][CH2:13][C:14]([N:6]1[CH2:7][C@@H:3]([OH:2])[CH2:4][C@@H:5]1[C:8]([O:10][CH3:11])=[O:9])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@H]1C[C@H](O)CN1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: c1ccccc1
Product: COC(=O)[C@H]1C[C@H](O)CN1C(=O)CCl
Reaction time: 0.5 h

Procedure:
To a suspension of Example 17A (100 g, 0.55 mol, 1 equivalent) in benzene (2.5 L), chloroacetyl chloride (62.4 g, 0.50 mol, 1 equivalent) was added dropwise at 20-25° C. The reaction mixture was refluxed for 3 hours. Then charcoal (2 g) was added, and the mixture was hot filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to get a solid. To this crude material, methyl tert-butyl ether (500 mL) was added and stirred for 30 minutes. The solid was collected by filtration, and the wet cake was dried in a vacuum tray dryer for 5 hours at about 50° C. to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.06-2.15 (m, 1H), 2.31-2.39 (m, 1H), 3.64 (d, 1H, J=11.1 Hz), 3.76 (s, 3H), 3.76-3.86 (m, 2H), 4.09 (s, 2H), 4.6-4.65 (m, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.[CH3:21][C:22]1[C:27]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:26][CH:25]=[C:24]([CH3:34])[N:23]=1>>[CH3:21][C:22]1[C:27]([N:28]2[CH2:33][CH2:32][N:31]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:20])=[CH:8][C:9]=3[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:30][CH2:29]2)=[CH:26][CH:25]=[C:24]([CH3:34])[N:23]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)n1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)n1
Yield: 35 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (189 mg) described in Preparation Example 22 and 1-(2,6-dimethylpyridin-3-yl)piperazine (113 mg) described in Preparation Example 94 and by the reaction and treatment in the same manner as in Example 87, the title compound (102 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([Br:13])[CH:7]=[C:8]([N+]([O-])=O)[CH:9]=1)([O-:3])=[O:2].[CH3:14][O-:15].[Na+]>CO>[Br:13][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([O:15][CH3:14])[CH:7]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 80 %

Procedure:
3,5-Dinitrobromobenzene (1.25 g, 5.06 mmol) was stirred in methanol (12 mL) and a solution of sodium methoxide (0.5 M in methanol, 12.6 mL) was added. The mixture was heated to 60° C. for 2 hours and cooled to RT. The mixture was quenched with hydrogen chloride solution (1 N) and extracted with dichloromethane. Evaporation and purification by silica chromatography using ethyl acetate and hexanes gave the desired compound (1.0 g, 80%). LCMS for C7H7BrNO3 (M+H)+: m/z=232.1.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.[CH3:22][O-:23].[Na+].[NH4+].[Cl-]>C1COCC1>[CH3:22][O:23][C:2]1[C:3]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: C[O-]
Reactant: COc1cnc(Cn2ccnc2-c2ncccn2)c(Cl)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cnc(Cn2ccnc2-c2ncccn2)c(OC)n1

Procedure:
To a solution of 2-[1-(3-chloro-5-methoxy-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine (30 mg, 0.094 mmol) in THF (5 mL) is added sodium methoxide (25% w/w in methanol, 0.5 mL). The mixture is refluxed for 1 hour. On cooling, saturated NH4Cl (0.7 mL) is added to quenched the reaction. Solvent is removed in vacuo and to the residue is added DCM (30 mL). The mixture is then dried and solvent removed to give 21 mg of 2-[1-(3,5-dimethoxy-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine as an oil. 1H NMR (CDCl3) 8.79 (d, 2H), 7.62 (s, 1H), 7.15–7.21 (m, 2H, 7.07 (s, 1H), 5.95 (s, 2H), 3.88 (s, 3H), 3.82 (s, 3H) I. 2-[1-(5-Methoxy-3-piperidin-1-yl-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine (Compound 10)
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[OH-].[Li+].[CH3:15][O:16][CH2:17][CH2:18][OH:19]>>[CH3:15][O:16][CH2:17][CH2:18][O:19][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: COCCO
Agent: [Li+]
Agent: [OH-]
Product: COCCOc1ccc(C(=O)O)cn1
Temperature: 40 °C
Yield: 67 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 67% yield starting from ethyl 6-chloronicotinate and 2-methoxyethanol. The reduction was performed using 3 equiv of lithium hydroxide while heating to 40° C. over weekend. The final aqueous solution was extracted with ethyl acetate in order to collect the product; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (d, 1 H), 8.13 (dd, 1 H), 6.91 (d, 1 H), 4.42-4.47 (m, 2 H), 3.62-3.68 (m, 2 H), 3.29 (s, 3 H); MS (ESI) m/z 198[M+H+].
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[C:17]=23)=[CH:20][C:21]=1[CH3:34]
Reactant: CN1CCNCC1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCN(C)CC4)c23)ccc1OCc1cccc(F)c1
Yield: 23 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methylphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate (prepared as described in Example 21) and N-methylpiperazine to give the title compound in 23% yield; NMR Spectrum: 2.09 (s, 3H), 2.28 (s, 3H), 2.50 (s, 4H), 2.77 (t, 2H), 4.42 (t, 2H), 5.16 (s, 2H), 7.00 (d, 1H), 7.16 (td, 1H), 7.31 (m, 2H), 7.43 (m, 3H), 8.16 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 492 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[Br:18]Br>ClCCl>[Br:18][C:8]1[O:9][C:10]2[C:2]([Br:1])=[CH:3][C:4]([CH3:17])=[CH:5][C:6]=2[C:7]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrBr
Reactant: Cc1cc(Br)c2occ(-c3ccccc3)c2c1
Solvent: ClCCl
Product: Cc1cc(Br)c2oc(Br)c(-c3ccccc3)c2c1

Procedure:
A solution of 86.6 g. (0.30 mole) of 7-bromo-5-methyl-3-phenylbenzofuran in 600 ml. of dichloromethane is treated dropwise over 45 minutes with 47.9 g. (0.30 mole) of bromine. After stirring one additional hour, the mixture is washed once with water (300 ml.) and thrice with 300 ml. portions of saturated sodium bicarbonate solution, dried, then evaporated to provide 2,7-dibromo-5-methyl-3-phenylbenzofuran as an oil which crystallizes from hexane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:18]/[O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])/[C:15](O)=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:34][C@@H:35]1[C:53](=[O:54])[N:37]2[C:38]([C:50]([OH:52])=[O:51])=[C:39]([CH2:42][O:43][C:44](=[O:49])[CH2:45][C:46](=[O:48])[CH3:47])[CH2:40][S:41][C@H:36]12>ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:18]/[O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])/[C:15]([NH:34][C@@H:35]2[C:53](=[O:54])[N:37]3[C:38]([C:50]([OH:52])=[O:51])=[C:39]([CH2:42][O:43][C:44](=[O:49])[CH2:45][C:46](=[O:48])[CH3:47])[CH2:40][S:41][C@H:36]23)=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1nsc(NC(=O)OC(C)(C)C)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)OC(C)(C)C)c3nsc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1
Reaction time: 0.33 h
Yield: 103.5 %

Procedure:
To a solution of 13 g of 2-(tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2(Z)-(tert-butoxycarbonylmethoxyimino)acetic acid in 100 ml of dichloromethane, 7 g of phosphorus pentachloride is added and the mixture is stirred for 20 minutes under ice-cooling. The reaction mixture is evaporated to dryness and to the residue is added hexane and the solvent is evaporated off again. The residue is dissolved in 5 ml of dichloromethane and the solution is added under ice-cooling to a solution prepared by allowing 10 g of 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid and 16 g of N,O-bistrimethylsilylacetamide to react in 200 ml of dichloromethane at room temperature for one hour. The mixture is stirred at the same temperature for one hour and the solvent is then evaporated under reduced pressure. The residue is dissolved in 300 ml of ethyl acetate and the solution is washed with water and then dried over anhydrous magnesium sulfate. Then, the solvent is evaporated off and the residue is triturated with hexane. Insoluble substance is collected by filtration to give 23 g of 7β-[2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2(Z)-(tert-butoxycarbonylmethoxyimino)acetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid.