Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][S:28][C@H:29]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)=[O:35])[CH2:30]2)[CH2:10]1)(C(C)(C)C)(C)C.Cl>CO.O1CCCC1.C(OCC)(=O)C>[OH:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([CH2:27][S:28][C@H:29]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=3)=[O:35])[CH2:30]2)[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CS[C@H]2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of (2S, 4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[{(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio}methyl]pyrrolidine (1.94 g) in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml) was added conc. hydrochloric acid (0.48 ml) at ambient temperature and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (50 ml) and the solution was washed three times with saturated aqueous sodium hydrogen carbonate (50 ml) and saturated aqueous sodium chloride (20 ml) successively, dried over magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (5:1 v/v) to give (2S, 4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[{(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio}-methyl]pyrrolidine (1.10 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])([OH:24])[CH3:23])[CH:3]=1.[CH:32]([NH:35]C(C)C)(C)[CH3:33].[Li].BrCC(N)=[O:43].[I-].[Na+]>C(OCC)C.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:10])=[O:11])[C:33](=[O:43])[CH2:32][NH2:35])=[C:4]([C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])([OH:24])[CH3:23])[CH:3]=1
Reactant: CC(C)NC(C)C
Reactant: NC(=O)CBr
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(C)(O)c2ccccc2Cl)cc1OC
Agent: [I-]
Agent: [Li]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(C(=O)CN)c2ccc(Cl)cc2C(C)(O)c2ccccc2Cl)cc1OC
Reaction time: 18 h

Procedure:
To 1.3 g of N-{4-chloro-2-[1-(2-chlorophenyl)-1-hydroxyethyl]phenyl}-3,4-dimethoxybenzenesulfonamide dissolved in diethyl ether are successively added, at −5° C., 1.3 ml of a 2M solution of lithium diisopropylamine in hexane, and 0.45 g of 2-bromoacetamide. After 18 hours at room temperature, 0.5 g of 2-bromoacetamide and 1.4 g of sodium iodide are successively added and the mixture is refluxed for 4 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 95/5 (v/v) dichloromethane/methanol mixture to give 0.51 g of the expected product.
Reaction SMILES: [CH:1]([C:3]1[N:4]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=O.[C:17]([N:34]([NH:36][CH3:37])[CH3:35])([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:23]1[C:22]2[CH:21]([CH2:20][O:19][C:17]([N:34]([CH3:35])[N:36]([CH2:1][C:3]3[N:4]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH3:37])=[O:18])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1cc2ccccc2n1CCC(=O)O
Reactant: CNN(C)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(Cc1cc2ccccc2n1CCC(=O)O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 2 h
Yield: 62 %

Procedure:
Compound 3 was synthesized from Compound 2 as follows. To a solution of Compound 2 (1.193 g, 5.492 mmol) and FmocN(Me)NHMe (2.147 g, 7.604 mmol, 1.38 equiv) in 1,2-dichloroethane (anhydrous, 25 mL) was added sodium triacetoxyborohydride (1.273 g, 6.006 mmol, 1.09 equiv). The resulting yellow suspension was stirred for 2 h and then quenched with sodium bicarbonate (saturated aqueous solution, 10 mL), followed by addition of hydrogen chloride (1 M aqueous solution) to pH 4. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (5×10 mL). The pooled organic extracts were dried over sodium sulfate, filtered, and concentrated to an orange oil. Purification by C18 silica gel chromatography (20-90% acetonitrile in water) yielded 3 as a waxy pink solid (1.656 g, 3.425 mmol, 62%). 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=7.4 Hz, 2H), 7.70-7.47 (br m, 3H), 7.42-7.16 (br m, 6H), 7.12-7.05 (m, 1H), 6.37 (s, 0.6H), 6.05 (s, 0.4H), 4.75-4.30 (br m, 4H), 4.23 (m, 1H), 4.10 (br s, 1H), 3.55 (br d, 1H), 3.11-2.69 (m, 5H), 2.57 (br s, 2H), 2.09 (br s, 1H). 13C NMR (101 MHz, CDCl3) δ 174.90, 155.65, 143.81, 141.42, 136.98, 134.64, 127.75, 127.48, 127.12, 124.92, 122.00, 120.73, 120.01, 119.75, 109.19, 103.74, 67.33, 66.80, 51.39, 47.30, 39.58, 39.32, 35.23, 32.10. HRMS (ESI) calcd for C29H30N3O4 [M+H]+: 484.2236. found: 484.2222.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[CH2:13][N:14]=[N+]=[N-])[CH3:10].[NH4+].[Cl-].C([O-])(=O)C=C>O.CCOCC.C(O)C>[CH2:9]([O:11][C:12]([C:13]1[NH:14][C:4]2[CH:3]=[C:2]([Cl:1])[S:6][C:5]=2[CH:7]=1)=[O:17])[CH3:10]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc(Cl)s1
Agent: C=CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cc2sc(Cl)cc2[nH]1

Procedure:
5-Chloro-thiophene-2-carbaldehyde was annulated according to Procedure H (aldehyde and azido-acetic acid ethyl ester added as ethanol solution (1.2 M of ester) such that reaction temperature maintained at 0-5° C.; reaction mixture allowed to warm to room temperature, stirred for 2 h, poured into cold saturated aqueous NH4Cl; after ether extractions, combined acrylate organic phases washed with water until aqueous phase was neutral; 0.5 M solution of crude acrylate heated for 1.5 h).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[C:13]1[CH2:25][CH3:26])(C)(C)C>FC(F)(F)C(O)=O>[CH2:25]([C:13]1[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=1)[CH3:26]
Reactant: CCc1nc2cnc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2cnc3ccccc3c2n1CCCCN

Procedure:
A solution of [4-(2-Ethyl-imidazo[4,5-c]quinolin-1-yl)-butyl]-carbamic acid tert-butyl ester of formula 5 obtained in step V in trifluoroacetic acid was stirred at 40° C. for 4 hrs. Reaction mixture was then poured on ice-water mixture and extracted with chloroform. Organic layer was dried over sodium sulphate and concentrated under deduced pressure to afford 4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine of formula 6.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[NH2:7][C@H:8]([C:13]([OH:15])=O)[C@H:9]([CH2:11][CH3:12])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[CH:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[ClH:2].[NH2:7][C@@H:8]([CH:9]([CH3:10])[CH2:11][CH3:12])[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: c1ccccc1
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(C)[C@H](N)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of phosphorus pentachloride (31.4 g, 0.151 mmol.) in anhydrous benzene (300 mL) was added L-isoleucine (19.67 g, 0.151 mmol.) under chilling with ice. The mixture was then stirred for 2 hours under chilling with ice, and further stirred for 17 hours at room temperature. The reaction mixture was chilled with ice and anhydrous aluminum chloride (60 g) was portionwise added. The mixture was then slowly heated to reflux temperature for a period of 2 hours. The mixture was refluxed for 3 hours, and then chilled with ice. The chilled reaction mixture was slowly added to a mixture of concentrated hydrochloric acid (45 mL) and ice (0.3 kg). The resulting mixture was stirred at 5° C. for 40 min. The precipitated crystals were collected by filtration and washed with benzene The washed crystals were dried in air to give 2-(S)-amino-3-methyl-1-phenyl-1-pentanone hydrochloride as a white crystalline product (29.2 g, yield: 85%).
Reaction SMILES: [CH:1]([N:3]([C:16](=[CH:22]O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:14][CH3:15])=O.Cl.C([NH2:27])=O>>[CH2:14]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:4]=1[N:3]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][N:27]=[CH:1]1)[CH3:15]
Reactant: NC=O
Reactant: CCOC(=O)C(=CO)N(C=O)c1c(CC)cccc1C(F)(F)F
Agent: Cl
Product: CCOC(=O)c1cncn1-c1c(CC)cccc1C(F)(F)F

Procedure:
1.3 g (3.9 mmol) of ethyl 2-(N-formyl-2-ethyl-6-trifluoromethylanilino)-3-hydroxyacrylate were heated for 4 hours at 150° C. with 20 ml of formamide and 5 ml of concentrated hydrochloric acid. After cooling, the mixture was extracted twice with diisopropyl ether, and the organic phase was washed with water, dried over sodium sulfate and evaporated. After chromatographic purification, 0.7 g (57% of theory) of ethyl 1-(2-ethyl-6-trifluoromethylphenyl)imidazole-5-carboxylate, a colorless oil, was obtained. The compound was identified by NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[O:4][NH2:5].Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13]>N1C=CC=CC=1.ClCCl>[C:15]1([O:14][C:12](=[O:13])[NH:5][O:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=2[Cl:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NOc1cccc(Cl)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NOc1cccc(Cl)c1Cl)Oc1ccccc1
Reaction time: 1 h
Yield: 83 %

Procedure:
9.10 g (51.1 mmole) of 2,3-dichlorophenoxyamine was dissolved in 7.5 ml of pyridine and 70 ml of dichloromethane, and the solution was cooled to -10° C. Then, 30 ml of a dichloromethane solution containing 7.28 g (46.5 mmole) of phenyl chloroformate was dropwise added thereto over a period of 1 hour, and the mixture was stirred at a temperature of from -10° to 25° C. for 6 hours. The solvent was distilled off under reduced pressure, and 300 ml of ethyl acetate was added. The mixture was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue thereby obtained was recrystallized from toluene/hexane, whereby 11.5 g of the desired product was obtained as light brown crystals (yield: 83%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH:7]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]([OH:18])=[O:17])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC(=O)OC(C)(C)C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cn(CC(=O)O)c2ccccc12
Temperature: 25 °C

Procedure:
1-tert-Butoxycarbonylmethyl-1H-indole-3-carboxylic acid ethyl ester (700 mg, 2.31 mmol) was dissolved in CH2Cl2 (12 mL), TFA (2.65 mL, 34.6 mmol) was added and the solution was stirred at RT over week end. CH2Cl2 and water were added, the layers were separated and the aqueous one re-extracted with CH2Cl2 (2×). The combined organic layers were dried with Na2SO4, filtered and concentrated to give the desired compound. TLC, Rf (EtOAc)=0.62; MS (LC/MS): 248.1 [M+H]+, 246.0 [M−H]−; tR (HPLC conditions a): 3.03 min.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:44]=[N:43][N:42]([CH2:45][CH2:46][CH3:47])[N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[CH:44]=[N:43][N:42]([CH2:45][CH2:46][CH3:47])[N:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cnn(CCC)n4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cnn(CCC)n4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-propyl-1,2,3-triazol-4-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.45 g) was dissolved in methylene chloride (9.0 ml), and to the solution was added dropwise a solution of m-chloroperbenzoic acid (174 mg) in methylene chloride (9.0 ml) at −78° C. The mixture was stirred for 15 minutes, and an aqueous solution of saturated sodium thiosulfate was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-propyl-1,2,3-triazol-4-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 276) (0.39 g).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:23]=[CH:22][C:17]([CH2:18][N:19]=[C:20]=[O:21])=[CH:16][CH:15]=1>>[N:1]1[C:10]2[C:5](=[C:6]([NH:11][C:20]([NH:19][CH2:18][C:17]3[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:25])[F:24])=[CH:23][CH:22]=3)=[O:21])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1cccc2nnccc12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2nnccc12

Procedure:
Prepared from cinnolin-5-amine (Sci Pharm. 1982, 50, 246) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 347 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([O:15][CH3:16])=[C:8]([CH2:12][C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([O:15][CH3:16])=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][C:13]1[NH:24][N:23]=[N:22][N:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1c(CC#N)cccc1OCc1c(C)cccc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1c(Cc2nnn[nH]2)cccc1OCc1c(C)cccc1C
Temperature: 90 °C

Procedure:
A mixture of 2-(3-(2,6-dimethylbenzyloxy)-2-methoxyphenyl)acetonitrile (Step D, 3.2 g, 12.7 mmol), sodium azide (0.86 g, 13.2 mmol) and ammonium chloride (0.696 g, 13.0 mmol) in dry DMF (10 ml) was heated under argon at 90° C. for 16 hours or until all the starting material is consumed, the reaction mixture was cooled, and concentrated under reduced pressure and purified by flash chromatography on a silica gel column (chloroform:methanol 9:1) to give semi solid product. The semi solid was stirred with 1:2 ethyl acetate:hexane (15 ml) for 10 minutes, and filtered to give product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][C:5]2[N:6]([CH3:12])[C:7](C(C)=C)=[N:8][C:4]=2[CH:3]=1.[Cl:16]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[CH3:28][C:29]([CH3:31])=[O:30]>O>[Cl:16][CH2:28][C:29]([C:7]1[N:6]([CH3:12])[C:5]2[CH:13]=[C:14]([Cl:15])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1)([OH:30])[CH3:31]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: C=C(C)c1nc2cc(Cl)c(Cl)cc2n1C
Reactant: CC(C)=O
Solvent: O
Product: Cn1c(C(C)(O)CCl)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 5,6-dichloro-1-methyl-2-isopropenyl-1H-benzimidazole (2.5 g) in acetone (30 mL) and water (6 mL) at room temperature was added trichloroisocyanuric acid (845 mg). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. After removal of the dessicant by filtration, concentration yielded an orange crude oil. The crude product was purified by flash chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: Cc1ccccc1Br
Product: Cc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromotoluene. MS (ESI): mass calcd. for C17H14FN3, 279.12; m/z found, 280.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.12 (s, 1H), 7.95 (m, 1H), 7.28-7.12 (m, 6H), 4.66 (s, 2H), 2.32 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:4]=1.[CH3:13][S-:14].[Na+].C(OCC)(=O)C>C(O)C.[Cl-].[Na+].O>[Cl:12][C:5]1[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=[C:3]([CH2:2][S:14][CH3:13])[CH:4]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1cc(Cl)cc(CBr)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSCc1cc(Cl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of 1-(bromomethyl)-3-chloro-5-nitrobenzene (10.0 g) in ethanol (200 mL) was treated at −20° C. with portions of sodium methanthiolat (3.32 g) and stirred for 3 hours at room temperature. The reaction mixture was treated with brine (100 mL) extrakted with ethyl acetate (300 mL), washed with water (2×100 mL) and, dried with sodium sulfate and evaporated to dryness. One obtained the title compound (8.6 g) which was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:24])=[C:15](OS(C)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH-:37].[Na+].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:24])=[C:15]([SH:37])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [SH-]
Reactant: COc1ccc(COC(=O)C2=C(OS(C)(=O)=O)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC(=O)C2=C(S)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
(a-1) To a solution of 16.5 g (31.3 mM) of p-methoxybenzyl 7β-phenylacetamido-3-methanesulfonyloxy-3-cephem-4-carboxylate in 70 ml of N,N-dimethylformamide were added a solution of 2.75 g (34.4 mM) of 70% sodium hydrosulfide in 30 ml of N,N-dimethylformamide and 6.06 g (47.0 mM) of diisopropylethylamine at -20° C., and the mixture was stirred at 0° C. for one hour. After the reaction, 1 l of water was added, the mixture was washed with ethyl acetate (200 ml×3), and the aqueous layer was adjusted to pH 1 with 3% hydrochloric acid and extracted with ethyl acetate (500 ml and 200 ml). The extract was washed with a saturated aqueous sodium chloride solution (300 ml×2) and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was dissolved in 200 ml of dichloromethane, and the solution was added dropwise to 700 ml of diethyl ether with stirring. The precipitate formed was collected by filtration to give 7.24 g of p-methoxybenzyl 7β-phenylacetamido-3-mercapto-3-cephem-4-carboxylate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[CH:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH:15]1([N:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[CH:7]3)[CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: ClCCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)ncn2CCCCN1CCN(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(1-cyclohexyl) piperazine (5.1 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.4 g compound (I-15) with a yield of 62.9%. ESI-MS [M+H]+: m/z 341.3.
Reaction SMILES: Br.C(O)(=[O:4])C.[Cl-].C([N:10]1C2[C:14](=[C:15]([OH:20])C=CC=2)[C:13](=[O:21])[CH2:12][CH:11]1CC=O)(=O)C.C1(C2SC(=O)CN=2)C=CC=CC=1.[C:37]1([C:43]2[S:44][C:45](=[O:65])[C:46](=[CH:48][CH2:49][CH:50]3[CH2:59][C:58](=[O:60])[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][C:56]=4[OH:61])[N:51]3[C:62](=[O:64])[CH3:63])[N:47]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>N1C=CC=CC=1>[C:43]([NH:47][CH:46]1[CH:48]2[CH:14]([CH:15]([OH:20])[CH:59]3[CH:50]([CH2:49]2)[N:51]([C:62](=[O:64])[CH3:63])[C:52]2[C:57](=[C:56]([OH:61])[CH:55]=[CH:54][CH:53]=2)[C:58]3=[O:60])[C:13](=[O:21])[C:12]([C:11]([NH2:10])=[O:4])=[C:45]1[OH:65])(=[S:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(=O)N1c2cccc(O)c2C(=O)CC1CC=C1N=C(c2ccccc2)SC1=O
Reactant: CC(=O)N1c2cccc(O)c2C(=O)CC1CC=O
Reactant: CC(=O)O
Agent: Br
Agent: O=C1CN=C(c2ccccc2)S1
Agent: [Cl-]
Solvent: c1ccncc1
Product: CC(=O)N1c2cccc(O)c2C(=O)C2C(O)C3C(=O)C(C(N)=O)=C(O)C(NC(=S)c4ccccc4)C3CC21

Procedure:
The starting material can be obtained by hydrogenation of 4-oxo-5-methoxy-1,4-dihydro-quinoline-2-acetic acid methyl ester to give 4-oxo-5-methoxy-1,2,3,4-tetrahydroquinoline-2-acetic acid methyl ester, saponification to give the free acid, acetylation to give 1-acetyl-4-oxo-5-methoxy-1,2,3,4-tetrahydro-quinoline-2-acetic acid, ether splitting by means of HBr/acetic acid, reaction into the chloride, Rosenmund reduction to give 1-acetyl-4-oxo-5-hydroxy-1,2,3,4-tetrahydro-quinoline-2-acetaldehyde, condensation with 2-phenyl-2-thiazolin-5-one to give 2-phenyl-4-[2-(1-acetyl-4-oxo-5-hydroxy-1,2,3,4-tetrahydro-2-quinolyl)-ethylidene]-2-thiazolin-5-one, condensation with acetonedicarboxylic acid monomethyl ester-monoamide to give 4-thiobenzamido-1,4,4a,5,5a,6,11,12-octahydro-3,10,12-trihydroxy-6-acetyl-1,11-dioxo-6-aza-naphthacene-2-carboxamide (mixture of stereoisomers), epimerization with pyridine to give 4-de-dimethylamino-4-thiobenzamido-6-acetyl-12a-de-hydroxy-6-aza-tetracycline and hydroxylation.