Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.O1CCOCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ccncc2)no1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ccncc2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.5 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(4-pyridinylmethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 105) (400 mg, 0.97 mmol) in hydrogen chloride in 1,4-dioxan (4M) (5 ml) was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. The solid was dissolved in fresh hydrogen chloride in 1,4-dioxan (4M) and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to afford the title compound as a yellow oil (390 mg).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[SH:13].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1F)[C:18]#[N:19]>O>[C:18]([C:17]1[CH:20]=[CH:21][C:22]([S:13][C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[C:15]([F:14])[CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: Sc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Sc2cccs2)c(F)c1
Temperature: 25 °C

Procedure:
Sodium hydride (1.80 g 60% dispersion in oil, 0.045 mol) was washed with petroleum ether then suspended in freshly degassed DMF (50 ml). Thiophene thiol (5.22 g, 0.045 mol) was added dropwise under nitrogen and the mixture was stirred until gas evolution ceased. 3,4-Difluorobenzonitrile (5.0 g, 0.036 mol) was added portionwise and the mixture was refluxed about 1.5 hours, after which the mixture was cooled to room temperature. The reaction mixture was poured into cold H2O and extracted with 3×100 ml ether. The ether extracts were washed with water and brine, then treated with decolorizing carbon and magnesium sulfate. After filtration and evaporation of the solvent the residual (8.46 g) oil crystallized.
Reaction SMILES: [ClH:1].C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:43][O:44][CH2:45][CH2:46][NH:47]C(OC(C)(C)C)=O)[C:11]([NH:13][CH:14]2[C:41](=[O:42])[N:16]3[C:17]([C:38]([OH:40])=[O:39])=[C:18]([CH2:21][S:22][C:23]4[N:27]([CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)[N:26]=[N:25][N:24]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O>CO>[ClH:1].[ClH:1].[ClH:1].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:43][O:44][CH2:45][CH2:46][NH2:47])[C:11]([NH:13][CH:14]2[C:41](=[O:42])[N:16]3[C:17]([C:38]([OH:40])=[O:39])=[C:18]([CH2:21][S:22][C:23]4[N:27]([CH2:28][CH2:29][NH2:30])[N:26]=[N:25][N:24]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCN)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Conc. hydrochloric acid (3.2 g.) was added to a solution of 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.5 g.) in methanol (50 ml.) and stirred at room temperature for 2 hours. After removing the solvent in vacuo, methanol was added to the residue. The mixture was concentrated in vacuo again. The precipitates were collected by filtration and washed with diethyl ether to give 7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-[(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid trihydrochloride (syn isomer, 2.8 g.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:13])[CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]=[CH:4][N:3]=1.[CH3:14][NH:15][CH3:16].Cl.C(OCC)(=O)C>ClCCl>[ClH:1].[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([OH:13])=[C:6]2[C:11]=1[C:2]([N:15]([CH3:16])[CH3:14])=[N:3][CH:4]=[N:5]2
Reactant: CNC
Reactant: Oc1ccc(Cl)c2c(Cl)ncnc12
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)c1ncnc2c(O)ccc(Cl)c12
Reaction time: 0.5 h

Procedure:
A solution of 4,5-Dichloro-8-quinazolinol (0.6 g, 2.8 mmol) in dichloromethane is added to a saturated solution of dimethylamine gas in dichloromethane. The reaction mixture is stirred for 30 minutes, re-saturated with dimethylamine gas, stirred for 30 minutes and concentrated in vacuo to obtain a yellow solid. The solid is added to a 2.5% hydrochloric acid/ethyl acetate mixture. The mixture is filtered and the filter cake is washed with water and dried in a vacuum oven to give the title product as a white solid, 0.35 g, mp 232° C. (dec.).
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7](=[O:18])[C@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[I-:19].CS[C:22]1[S:26][CH:25]=[CH:24][S+:23]=1>O>[I-:19].[S:23]1[CH:24]=[CH:25][S:26][C:22]1=[N+:9]([CH3:10])[CH:8]([C:7]([O:6][CH3:5])=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN[C@@H](Cc1ccccc1)C(=O)OC
Reactant: CSc1scc[s+]1
Agent: [I-]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(Cc1ccccc1)[N+](C)=c1sccs1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To 100 ml of acetone, 2.2 g of N-methylphenylalanine methyl ester was dissolved, and 2.0 g of 2-methylthio-1,3-dithiolium iodide was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The residue was dissolved in water. The aqueous layer was washed with ethyl acetate, and then water was distilled off under reduced pressure, whereby 1.7 g (yield: 52%) of N-(1,3-dithiol-2-ylidene)-N-methyl-N-(2-phenyl-1-methoxycarbonylethyl)ammonium iodide (Compound No. 5) was obtained as oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[S:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:14]([CH:11]1[CH2:12][CH2:13][S:8][CH2:9][CH2:10]1)[OH:15]
Reactant: Brc1ccccn1
Reactant: O=CC1CCSCC1
Product: OC(c1ccccn1)C1CCSCC1

Procedure:
Prepared according to the method of Example 225, Step A, from 2-bromopyridine and tetrahydro-2H-thiopyran-4-carbaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([CH3:12])[C:9]([OH:11])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][C:56]1[CH:57]=[C:58]([C:62]2[N:71]=[C:70]([NH:72][C:73]3[CH:74]=[C:75]4[C:79](=[CH:80][CH:81]=3)[N:78]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[N:77]=[CH:76]4)[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[N:63]=2)[CH:59]=[CH:60][CH:61]=1>C(Cl)Cl>[C:1]([O:5][C:6]([C@H:8]([CH3:12])[C:9]([NH:55][C:56]1[CH:57]=[C:58]([C:62]2[N:71]=[C:70]([NH:72][C:73]3[CH:74]=[C:75]4[C:79](=[CH:80][CH:81]=3)[N:78]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[N:77]=[CH:76]4)[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[N:63]=2)[CH:59]=[CH:60][CH:61]=1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](C(=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of (R)-2-(tert-butoxycarbonyl)propanoic acid (21 mg, 0.11 mmol), PyBOP® (57 mg, 0.11 mmol), DIEA (49 μL, 0.28 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired product tert-butyl 5-(2-(3-((R)-2-(tert-butoxycarbonyl)propanamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (95 mg, 69%).
Reaction SMILES: [C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1.[I:16]Cl>CO>[I:16][C:14]1[C:12](=[O:13])[NH:11][C:9](=[O:10])[N:8]([CH:15]=1)[C@@H:1]1[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: ClI
Reactant: O=c1ccn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]1
Solvent: CO
Product: O=c1[nH]c(=O)n([C@H]2CC[C@@H](CO)O2)cc1I
Reaction time: 2.75 h
Yield: 66 %

Procedure:
Dideoxyuridine (2.122 g, 10.0 mmol) was dissolved in 30 mL of warm methanol and, after cooling to 25°, iodine monochloride (4.06 g, 25 mmol, 2.5 eq, Fisher) in methanol (20 mL) was added over 5 min. The dark purple reaction mixture was heated in a 50° bath under nitrogen for 20 min and then immediately cooled in an ice-water bath. After standing without stirring for 165 min, the resulting precipitate was collected by filtvration and washed with cold methanol (2×10 mL). Vacuum-drying overnight afforded 2.232 g (66%) of iodide 47 as off-white microcrystals. This material was used without further purification in the next reaction, but other preparations were purified by chomatography or recrystallization from boiling methanol (30 mL/g) to give white needles (mp d 160-164°). NMR indicated that the crude precipitate was homogeneous, but also that the 5'-hydroxyl proton was very broad due to exchange catalyzed by trace impurities. Chomatographed or recrystallized materials afforded spectra in which this proton was, as usual, a sharp triplet.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1
Reactant: Cc1[nH]cnc1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1[nH]cnc1-c1ccc(N)cc1
Yield: 88 %

Procedure:
Sixty grams of 5-methyl-4-(4-nitrophenyl)-1-H-imidazole dissolved in methanol was hydrogenated in the presence of 0.7 gm of 5% Pd catalyst at atmospheric pressure and at room temperature. When the calculated amount of hydrogen was taken up, the catalyst was filtered off, and the solution was evaporated to dryness to yield 45 gm of 5-methyl-4-(4-aminophenyl)-1-H-imidazole.
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])([O-:5])=[O:4].O>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[C:6]([N+:3]([O-:5])=[O:4])[CH:11]=1
Reactant: BrBr
Reactant: COc1ccccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 87 %

Procedure:
Bromine, Br2 (16 ml, 311 mmol) was added in small portions to a solution of 2-nitroanisole (17.1 ml, 140 mmol) in glacial acetic acid (80 ml). The reaction mixture was then heated at 60° C. for one hour. The reaction was poured into 400 ml water, and extracted with 600 ml diethyl ether/600 ml saturated NaHSO3 (aqueous). The organic layer was washed with NaHSO3 solution, then with water, dried over sodium sulfate, and concentrated under vacuum. The residue was recrystallized from diethyl ether to give 28.4 g (87%) of 4-bromo-2-nitroanisole. 1H NMR (300 MHz, CDCl3) δ7.970 (1H, d, J=2.5 Hz), 7.64 (1H, dd, J=8.9, 2.4 Hz), 7.00 (1H, d, J=8.9 Hz), 3.96 (3H, s).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[OH:17].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][O:17][C:9]1[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=1[CH3:7]
Reactant: COC(=O)CBr
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
A solution of 15.76 ml (171 mmol) of methyl bromoacetate and 25.0 g (163 mmol) of 2-methyl-4-nitrophenol in 300 ml dry acetonitrile was treated with 61.3 g (188 mmol) Cs2CO3 and stirred at RT for 4 h. The mixture was filtered, washed with acetonitrile and evaporated. The residue was suspended in 700 ml CH2Cl2, filtered and evaporated to give 36.4 g of (2-methyl-4-nitro-phenoxy)-acetic acid methyl ester as yellow crystals.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:21]=3)[C:10]=2[O:9]1
Reactant: CNCC1Cc2cccc(Br)c2O1
Reactant: COc1cccc(B(O)O)c1
Product: CNCC1Cc2cccc(-c3cccc(OC)c3)c2O1

Procedure:
The title compound was prepared (0.41 g, 49%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 3-methoxyphenylboronic acid (0.188 g, 1.24 mmol). mp 148-151° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][S:16][C:10]=2S[CH2:8][CH2:7]1.OO.[S:19]([O-:22])(O)=[O:20].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][S:16][C:10]=2[S:19](=[O:22])(=[O:20])[CH2:8][CH2:7]1
Reactant: O=S([O-])O
Reactant: O=C1c2ccsc2SCCN1CCCCCl
Agent: OO
Agent: [Na+]
Solvent: O=CO
Product: O=C1c2ccsc2S(=O)(=O)CCN1CCCCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.4 g of 4-(4-chlorobutyl)-2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one in 100 ml of formic acid was added 2.9 ml of 30% hydrogen peroxide and the mixture was stirred for 3 hours at room temperature. Then, the mixture was poured into ca. 3% sodium hydrogensulfite solution and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off to give 3.5 g of 4-(4-chlorobutyl)-2,3-dihydrothieno-[3,2-f]1,4-thiazepin-5(4H)-one 1,1-dioxide as a pale yellow oil.
Reaction SMILES: [C:1]([OH:7])(=O)/[C:2](=[CH:4]/[CH3:5])/[CH3:3].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Cl-].[Li+].[CH:24]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1)([CH3:26])[CH3:25]>O1CCCC1>[CH:24]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[N:28]1[C:1](=[O:7])/[C:2](/[CH3:3])=[CH:4]/[CH3:5])([CH3:26])[CH3:25]
Reactant: CC(C)[C@@H]1COC(=O)N1
Reactant: C/C=C(\C)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C/C=C(\C)C(=O)N1C(=O)OC[C@H]1C(C)C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A cooled (−20° C.) solution of tiglic acid (2.005 g, 20.031 mmol) in anhydrous tetrahydrofuran (50 mL) was sequentially treated with triethylamine (6.1 mL, 44.068 mmol) and dropwise pivaloyl chloride (2.7 mL, 22.034 mmol). After stirring at −20° C. for 30 min, lithium chloride (1.019 g, 24.037 mmol) and (R)-(+)-4-isopropyl-2-oxazolidinone (2.587 g, 20.031 mmol) were added. The reaction mixture was allowed to slowly warm to room temperature, stirred for 3 days and was then quenched with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (3.307 g, 78%) as a colourless solid. 1H NMR (300 MHz, CDCl3): δ 0.92 (d, J=6.9 Hz, 3H), 0.94 (d, J=7.1 Hz, 3H), 1.83 (d, J=6.9 Hz, 3H), 1.93 (s, 3H), 2.38 (d of heptet, J=6.9, 4.2 Hz, 1H), 4.19 (dd, J=8.9, 4.6 Hz, 1H), 4.33 (app t, J=8.9 Hz, 1H), 4.49-4.58 (m, 1H), 6.23 (q, J=7.1 Hz, 1H).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.Br[CH2:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[CH3:10][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:23][CH2:24][C:25](=[O:26])[NH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: O=C(Cl)CCBr
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1ccc(N2CCC(=O)N2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19455.8 %

Procedure:
10 g of p-tolylhydrazine hydrochloride are dissolved in 100 ml of anhydrous CH2Cl2. The solution is cooled to 0° C. and 19 ml of DBU and then 6.5 mg of 3-bromopropionyl chloride are added. The mixture is stirred at ambient temperature for one hour. The reaction medium is poured onto water, extraction is carried out with CH2Cl2 and then purification is carried out by chromatography on a silica column eluted with an AcOEt/petroleum ether (v/v; 50/50) mixture. 1.3 g of crystals are obtained.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:30](=[O:31])[N:5]2[C:6]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:7](/[CH:10]=[CH:11]\[CH2:12][CH3:13])[CH2:8][S:9][C@H:4]12.C([O-])(O)=O.[Na+].[NH2:37][C:38]1[S:39][CH:40]=[C:41](/[C:43](=[N:56]/[O:57][CH3:58])/[C:44](ON2C3C=CC=CC=3N=N2)=[O:45])[N:42]=1>C(OCC)(=O)C>[NH2:37][C:38]1[S:39][CH:40]=[C:41](/[C:43](=[N:56]/[O:57][CH3:58])/[C:44]([NH:2][CH:3]2[C:30](=[O:31])[N:5]3[C:6]([C:14]([O:16][CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:15])=[C:7](/[CH:10]=[CH:11]\[CH2:12][CH3:13])[CH2:8][S:9][C@H:4]23)=[O:45])[N:42]=1
Reactant: CC/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CO/N=C(\C(=O)On1nnc2ccccc21)c1csc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.8 %

Procedure:
A suspension of diphenylmethyl 7-amino-3-[(Z)-1-butenyl]-3-cephem-4-carboxylate hydrochloride (1.41 g, 3.1 mmoles) in ethyl acetate (20 ml) was shaken with aqueous NaHCO3 to give a clear two-layer solution. The organic layer was separated, washed with water and then an aqueous saturated NaCl solution, and dried over MgSO4. To the dried filtrate was added 1-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetoxy]benzotriazole (1.27 g, 4.0 mmoles), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered and the filtrate was washed with aqueous NaHCO3, water and a saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The residue was chromatographed on a silica gel column (40 g) with 3:1 CHCl3 -ethyl acetate to yield 1.7 g (91%) of the title compound. TLC (silica gel): Rf 0.25 (1:1 CHCl3 -ethyl acetate).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[NH:10][CH:9]=[C:8]2[C:16]1[N:24]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=1.I[CH3:36].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[N:10]([CH3:36])[CH:9]=[C:8]2[C:16]1[N:24]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=1
Reactant: COc1cc(OC)c2[nH]cc(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.028 g of sodium hydride at 60% in oil is added, in small portions, to solution of 0.26 g of 2-(5,7-dimethoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 11.5 ml of dimethylformamide. The suspension is agitated for approximately 1 hour at around 20° C. and then 0.04 ml of iodomethane is added. After agitation for approximately 18 hours at around 20° C., the mixture is run into 100 ml of a mixture of ice plus water, and extracted with three times 75 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 0.3 g of 2-(5,7-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a foam, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].[F:21][C:22]1[CH:27]=[C:26](F)[C:25]([F:29])=[CH:24][C:23]=1[S:30]([N:33]([CH3:39])[C:34]1[S:38][N:37]=[CH:36][N:35]=1)(=[O:32])=[O:31]>CN(C)C=O.O>[NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[O:18][C:26]3[C:25]([F:29])=[CH:24][C:23]([S:30]([N:33]([CH3:39])[C:34]4[S:38][N:37]=[CH:36][N:35]=4)(=[O:31])=[O:32])=[C:22]([F:21])[CH:27]=3)=[CH:10][C:4]=2[N:3]=1
Reactant: CN(c1ncns1)S(=O)(=O)c1cc(F)c(F)cc1F
Reactant: Nc1nc2cc(-c3cc(Cl)ccc3O)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ncns1)S(=O)(=O)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccc3[nH]c(N)nc3c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 2-(2-amino-1H-benzo[d]imidazol-5-yl)-4-chlorophenol (0.40 g, 1.5 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added sodium hydride (60% w/w dispersion in mineral oil, 0.07 g, 1.8 mmol). The mixture was allowed to warm to ambient temperature and stirred for 1 h. 2,4,5-Trifluoro-N-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.52 g, 1.7 mmol) was added and the mixture was stirred at ambient temperature for 16 h. The mixture was partitioned between ethyl acetate (200 mL) and water (20 mL). The organic phase was washed with water (10 mL) and brine (2×10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-10% gradient of methanol in ethyl acetate, followed by trituration in hexanes. The solid thus obtained was suspended in water (5 mL) and lyophilized to afford 4-(2-(2-amino-1H-benzo[d]imidazol-5-yl)-4-chlorophenoxy)-2,5-difluoro-N-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a beige solid in 63% yield (0.344 g): 1H NMR (300 MHz, CDCl3) δ10.78 (br s, 1H), 8.42 (d, J=1.9 Hz, 1H), 7.94-7.86 (m, 1H), 7.52-7.48 (m, 1H), 7.45-7.37 (m, 1H), 7.29 (dd, J=8.7, 1.6 Hz, 1H), 7.13 (s, 1H), 7.10-6.99 (m, 2H), 6.91 (d, J=8.1 Hz, 1H), 6.25 (s, 2H), 3.31 (s, 3H); 19F NMR (282 MHz, DMSO-d6) δ −108.7 (d, J=15.0 Hz, 1F), −135.1 (d, J=15.1 Hz, 1F); MS (ES+) m/z 548.7 (M+1), 550.7 (M+1).