Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:30][CH2:29][C@:12]34[C:13]5[C:14]6[O:28][C@H:11]3[C@@H:10]([NH:31][CH3:32])[CH2:9][CH2:8][C@@:7]4([OH:33])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:36]=[C:37]([CH2:42][S:43](Cl)(=[O:45])=[O:44])[CH:38]=[CH:39][C:40]=1[Cl:41]>N1C=CC=CC=1>[CH:1]1([CH2:4][N:5]2[CH2:30][CH2:29][C@:12]34[C:13]5[C:14]6[O:28][C@H:11]3[C@@H:10]([N:31]([CH3:32])[S:43]([CH2:42][C:37]3[CH:38]=[CH:39][C:40]([Cl:41])=[C:35]([Cl:34])[CH:36]=3)(=[O:45])=[O:44])[CH2:9][CH2:8][C@@:7]4([OH:33])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[CH2:2][CH2:3]1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: CN[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O[Si](C)(C)C(C)(C)C)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Solvent: c1ccncc1
Product: CN([C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O[Si](C)(C)C(C)(C)C)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5)S(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
203.9 mg of 17-cyclopropylmethyl-3-tert-butyldimethylsilyloxy-14β-hydroxy-4,5α-epoxy-6α-(methylaminomorphinan 108 obtained in reference example 91 was dissolved in 3 ml of pyridine followed by the addition of 124 mg of 3,4-dichlorophenylmethanesufonylchloride and stirring for 30 minutes at room temperature. After concentrating the reaction system, 3 ml of saturated aqueous sodium bicarbonate and 3 ml of chloroform were added to separate layers, after which the aqueous layer was extracted twice with 3 ml of chloroform. After drying with anhydrous sodium sulfate, the organic layer was concentrated to obtain the oily crude product. This was then purified with silica gel column chromatography (30 g benzene/ethyl acetate=5/1) to obtain 235.4 mg of the target compound (yield: 78%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:24][NH2:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1cc(F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Fc1cc(CNc2nccc(-n3cnc4ccccc43)n2)cc(C(F)(F)F)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-fluoro-5-trifluoromethylbenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 388.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.58 (s, 1H); 8.46 (d, J=5.4 Hz, 1H); 7.99 (br s, 1H); 7.86 (d, J=8.7 Hz, 1H); 7.49 (s, 1H); 6.90 (d, J=5.5 Hz, 1H); 5.88 (br s, 1H); 4.82 (d, J=6.2 Hz, 2H).
Reaction SMILES: [F:1][C:2](S(C1C=CC=CC=1)(=O)=O)([F:4])[F:3].[CH3:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.C(O[K])(C)(C)C>CN(C=O)C>[CH3:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:2]([F:4])([F:3])[F:1])[OH:20])=[CH:17][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)C(F)(F)F
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: Cc1ccc(C(O)(c2ccccc2)C(F)(F)F)cc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Into a dry Schlenk flask under an argon atmosphere, was added 7 mL DMF solution of phenyl trifluoromethyl sulfone (1a, 420 mg, 2 mmol) and 4-methylbenzophenone (196 mg, 1 mmol) at −50° C., was added 3 mL DMF solution of tBuOK (280 mg, 2.5 mmol). The reaction flask was then sealed and the reaction mixture was then stirred from −50° C. for 1 h, followed by stirring at −50° C. to room temperature overnight. The reaction mixture was quenched with 10 mL of ice water, and extracted with ether (20 ml×3). The combined ether phase was washed with saturated NH4Cl aqueous solution, followed by washing with water. After drying over MgSO4, the ether solvent was removed under vacuum. The crude product was further purified by column chromatography (hexanes/ether=9/1) to give 225 mg of product, 4-methyl-α-phenyl-α-(trifluoromethyl)benzenemethanol as a colorless oily liquid, yield 85%. 1H NMR (CDCl3): δ 2.36 (s, 3H); 2.89 (s, 1H); 7.17–7.51 (m, 9H). 19F NMR (CDCl3): δ −74.4. MS: 266 (M+).
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([O:28][CH:29]2[CH2:32][NH:31][CH2:30]2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16]>C(Cl)Cl>[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([O:28][CH:29]2[CH2:30][N:31]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:32]2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(OC2CNC2)c2c(c1)OC(C)(C)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OC2CN(S(C)(=O)=O)C2)c2c(c1)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
Et3N (400 mg, 2.87 mmol) and methane sulfonyl chloride (75 uL, 0.97 mmol) were added to a solution of 4-(azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (193c) (303 mg, 0.97 mmol) in CH2Cl2 (15 mL). The mixture was stirred at room temperature for 2 hr, quenched with 1N aqueous HCl (60 mL) and extracted with CH2Cl2 (60 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatograph to give a white solid (197 mg, 57% yield). 1H NMR (400 MHz, CDCl3) δ 7.10 (s, 1 H) 6.75 (s, 1 H) 5.02 (d, J=6.06 Hz, 1 H) 4.34 (dd, J=8.46, 6.69 Hz, 2 H) 4.08 (dd, J=8.72, 4.93 Hz, 2 H) 3.89 (s, 3 H) 3.00 (s, 2 H) 2.93 (s, 3 H) 1.50 (s, 6 H).
Reaction SMILES: [C:1]([O:4][N:5]=[C:6]([C:23](=O)[CH2:24]Br)[C:7]([O:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:3])[CH3:2].[NH2:27][C:28]([NH2:30])=[S:29]>CN(C)C(=O)C>[C:1]([O:4][N:5]=[C:6]([C:23]1[NH:30][C:28](=[NH:27])[S:29][CH:24]=1)[C:7]([O:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)ON=C(C(=O)CBr)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: NC(N)=S
Solvent: CC(=O)N(C)C
Product: CC(=O)ON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(=N)[nH]1
Yield: 43 %

Procedure:
In 20 ml of N,N-dimethylacetamide there were dissolved 26.5 g of benzhydryl 2-acetoxyimino-4-bromo-3-oxobutyrate and, under ice-cooling and stirring, 4.81 g of thiourea were added. The mixture was stirred at room temperature for 3 hours and 15 minutes, after which it was washed well with 80 ml of ether. The ether was discarded after being removed by decantation. The above procedure was carried out once again and the mixture was poured into 100 ml of water, whereupon crystals separated out. After loosening, the crystals were recovered by filtration and washed with ether, a small amount of ethyl acetate and ether in the order mentioned. By the above procedure there were obtained 10.738 g of crystals of the captioned compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]([CH3:47])[C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40]>>[CH3:37][N:38]([CH3:47])[C:39]([N:41]1[CH2:42][CH2:43][N:44]([C:31]([N:12]2[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=2[O:34][CH2:35][CH3:36])=[O:32])[CH2:45][CH2:46]1)=[O:40]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)N(C)C)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazine-1-carboxylic acid dimethylamide (Aldrich) to give the title compound. LC-MS: 664.3 [(M+H)+]
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)(=O)[CH3:2].C([O-])([O-])=O.[K+].[K+].ClCC[CH2:35][N:36]1[CH2:41][CH2:40][N:39]2[C:42]([C:45]([F:48])([F:47])[F:46])=[N:43][N:44]=[C:38]2[CH2:37]1>CN(C=O)C.O>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:1][CH2:2][CH2:35][N:36]4[CH2:41][CH2:40][N:39]5[C:42]([C:45]([F:48])([F:46])[F:47])=[N:43][N:44]=[C:38]5[CH2:37]4)[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OC(C)=O
Reactant: FC(F)(F)c1nnc2n1CCN(CCCCl)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCn2c(nnc2C(F)(F)F)C1
Temperature: 80 °C
Yield: 45.5 %

Procedure:
To a mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate (0.62 g) and K2CO3 (0.35 g) in 10 mL of DMF was added 7-(3-chloropropyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.68 g) at rt. The reaction mixture was heated at 80° C. for 6 h, diluted with water and extracted with CH2Cl2. The combined organic phases were dried over anhydrous Na2SO4 for 1 h, and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a white solid (0.43 g, 40.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 552.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.80 (m, 2H), 2.46 (t, J=4.2 Hz, 2H), 2.78 (t, J=3.6 Hz, 2H), 3.58 (s, 2H), 4.03 (s, 3H), 4.10 (t, J=4.2 Hz, 2H), 4.15 (t, J=3.6 Hz, 2H), 7.16 (s, 1H), 7.26 (s, 1H), 7.45 (s, 1H), 7.57 (m, 1H), 7.91 (m, 1H), 8.64 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11](F)=[N:12][C:13]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[CH:14][C:15]=1[NH:16][CH2:17][C@@H:18]([OH:20])[CH3:19])=O.[NH2:31][NH2:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:10]2[C:11](=[N:12][C:13]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[CH:14][C:15]=2[NH:16][CH2:17][C@@H:18]([OH:20])[CH3:19])[NH:32][N:31]=1
Reactant: NN
Reactant: C[C@H](O)CNc1cc(Oc2ccc(F)cc2F)nc(F)c1C(=O)c1ccccc1Cl
Product: C[C@H](O)CNc1cc(Oc2ccc(F)cc2F)nc2[nH]nc(-c3ccccc3Cl)c12

Procedure:
Crude (S)-(2-Chloro-phenyl)-[6-(2,4-difluoro-phenoxy)-2-fluoro-4-(2-hydroxy-propylamino)-pyridin-3-yl]-methanone (837 mg, 1.92 mmol) was treated with hydrazine using the procedure of step 5 of Example 9 to afford 148 mg of (S)-1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-b]pyridin-4-ylamino]-propan-2-ol. Mass spec., M+1=432. Mp=237.9
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][C:24]([CH3:27])([NH2:26])[CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][C:24]([NH:26][S:29]([CH3:28])(=[O:31])=[O:30])([CH3:27])[CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(N)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
Triethylamine (1.77 mL, 12.7 mmol) was added to a solution of N1-(2-chloro-3-nitroquinolin-4-yl)-2-methylpropane-1,2-diamine (2.5 g, 8.5 mmol) in dichloromethane (25 mL), and the resulting solution was cooled to 0° C. and stirred for five minutes. Methanesulfonyl chloride (1.07 g, 9.33 mmol) was added in portions over a period of five minutes, and the reaction was allowed to warm to ambient temperature and stirred overnight. An analysis by high-performance liquid chromatography (HPLC) indicated the reaction was incomplete, and additional methanesulfonyl chloride (0.5 equivalent) was added. The reaction was stirred for two hours and again determined to be incomplete. Additional methanesulfonyl chloride (0.5 equivalent) and triethylamine (1.5 equivalents) were added, and the reaction was stirred for two hours and then diluted with dichloromethane. The resulting solution was washed twice with brine and twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 3.1 g of N-{2-[(2-chloro-3-nitroquinolin-4-yl)amino]-1,1-dimethylethyl}methanesulfonamide as a yellow solid.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(OC(C1C2O[C:18]([C:21](=[O:24])[CH2:22]Br)=CC=2C=CC=1)C)(=O)C>C(OCC)C>[C:1]([NH:5][CH2:18][C:21]([CH2:22][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(=O)OC(C)c1cccc2cc(C(=O)CBr)oc12
Solvent: CCOCC
Product: CC(C)(C)NCC(=O)CNC(C)(C)C
Reaction time: 20 h

Procedure:
0.9 g of tertbutylamine was added dropwise at 10°C at a stirred solution of 0.975 g of 7-(1'-acetoxyethyl)-2-bromoacetylbenzofuran (prepared as described in the penultimate paragraph of part A of Example 1) in 20 ml of dry diethyl ether. The mixture was then allowed to stand at 0°C for 20 hours. The cold solution was filtered and the filtrate extracted with dilute hydrochloric acid. The acidic extract was made basic with dilute aqueous sodium hydroxide solution and extracted twice with diethyl ether. The combined extracts were washed with water and with brine and then dried over anhydrous sodium sulphate. The sodium sulphate was filtered off, the filtrate evaporated to dryness under reduced pressure and the crude, unstable 7-(1'-acetoxyethyl)-2-benzofuranyl, (tertbutylaminomethyl) ketone obtained was used in the process without further purification.
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:31]([C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1)([O-:33])=[O:32].C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[S:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=1)(=[O:41])=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
A mixture of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (200 mg, 0.474 mmol), 3-nitrophenylsulphonyl chloride (105 mg, 0.474 mmol), diisoproylethylamine (0.084 mL, 0.474 mmol) and dimethylaminopyridine (˜1 mg) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature over 16 hours under an Argon atmosphere. The reaction was evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous hydrochloric acid (1N). After separating the phases, the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 1:1 ethyl acetate : hexane. Fractions containing the product were combined, evaporated in vacuo and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro [2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(3-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (246 mg, 86%). H1-NMR (chloroform-D3): 0.98 (m, 6H), 1.68 (m, 7H), 2.99 (m, 5H), 3.73 (m, 2H), 3.96 (m, 4H), 4.27 (m, 1H), 4.86 (d, 1H), 5.07 (m, 1H), 5.69 (d, 1H), 7.27 (m, 5H), 7.84 (m, 1H), 8.16 (d, 1H), 8.57 (d, 1H), 8.76 (s, 1H). MS (ESI): 630(M+Na).
Reaction SMILES: C(Cl)(Cl)Cl.[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]4[C:41]5[C:36](=[C:37]([NH2:42])[CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][C:33]4=[O:43])[CH2:26][CH2:25]3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.[C:44](Cl)(=[O:46])[CH3:45].C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]4[C:41]5[C:36](=[C:37]([NH:42][C:44]([CH3:45])=[O:46])[CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][C:33]4=[O:43])[CH2:26][CH2:25]3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To 2 mL of a chloroform solution containing 60 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 14 mg of triethylamine and 11 mg of acetyl chloride were added, and stirred at room temperature for 2 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 60 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-acetamino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow foam.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:6]([CH2:31][CH:32]2[CH2:34][CH2:33]2)[C:5]=1[OH:35])=[O:3].[C:36](OCC)(=O)C.CCCCCC>>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:16][C:15]1[CH:23]=[CH:24][CH:25]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:29]=[CH:30][C:4]([C:2]([NH2:1])=[O:3])=[C:5]([O:35][CH3:36])[C:6]=2[CH2:31][CH:32]2[CH2:33][CH2:34]2)[C:14]=1[CH2:26][CH2:27][CH3:28])[CH3:22]
Reactant: CCCc1c(OCCCOc2ccc(C(N)=O)c(O)c2CC2CC2)cccc1OCC(=O)OCC
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)cccc1OCC(=O)OCC

Procedure:
The compound of Example 70 is exposed to the conditions described in Example 25. Chromatography of the crude product on silica gel using ethyl acetate/hexane, (3:7) as eluant affords the product.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[C:20](=[N:25][OH:26])[C:21](=O)[CH2:22]Br)[C@H:4]2[S:3]1.[NH2:29][C:30]([NH2:32])=[S:31]>C(O)C>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[C:20](=[N:25][OH:26])[C:21]3[N:29]=[C:30]([NH2:32])[S:31][CH:22]=3)[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]2S1
Reactant: NC(N)=S
Solvent: CCO
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2S1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-hydroxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (a mixture of syn and anti isomers) (0.51 g.) in ethanol (10 ml.) was added thiourea (0.068 g.), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and water with stirring, and the ethyl acetate layer was separated. The remaining aqueous layer was adjusted to pH 7 and extracted with ethyl acetate. The ethyl acetate layer and extract were combined together, washed with water, dried over magnesium sulfate and then concentrated. The residue was pulverized in diethyl ether, collected by filtration and then dried to give pale brown powder of 2,2,2-trichloroethyl 2-methyl-7-[2-hydroxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as 2,2,2-trichloroethyl 2-methyl-7-[2-hydroxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), mp 175° to 178° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][CH2:7]2.C1COCC1.[Li]CCCC.[Li]C(C)(C)C.C(O[B:37]1[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]1)(C)C>CCCCC>[C:12]1([NH:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[B:37]3[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]3)[CH2:7][CH2:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1cccc2c1C(Nc1ccccc1)CC2
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1(C)OB(c2cccc3c2C(Nc2ccccc2)CC3)OC1(C)C
Reaction time: 1 h

Procedure:
To a solution of 2.50 g (8.70 mmol) of 7-bromo-N-phenyl-2,3-dihydro-1H-inden-1-amine in 50 ml THF 3.50 ml (8.70 mmol) of 2.5M nBuLi in hexanes was added at −80° C. in argon atmosphere. The reaction mixture was then stirred for 1 h at this temperature. Further on, 11.1 ml (17.8 mmol) of 1.7M tBuLi in pentane was added, and the reaction mixture was stirred for 1 h. Then, 3.23 g (17.4 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added. After that the cooling bath was removed, and the resulting mixture was stirred for 1 h at room temperature. To the formed mixture 10 ml of water was added, and the resulting mixture was evaporated to dryness. The residue was diluted with 200 ml of water, and the title product was extracted with 3×50 ml of ethyl acetate. The combined organic extract was dried over Na2SO4 and evaporated to dryness. Yield 2.80 g (96%) of a light yellow oil. Anal. calc. For C21H26BNO2: C, 75.24; H, 7.82; N, 4.18. Found: C, 75.40; H, 8.09; N, 4.02. 1H NMR (CDCl3): δ 7.63 (m, 1H, 6-H in indane); 7.37-7.38 (m, 1H, 4-H in indane); 7.27-7.30 (m, 1H, 5-H in indane); 7.18 (m, 2H, 3,5-H in phenyl); 6.65-6.74 (m, 3H, 2,4,6-H in phenyl); 5.20-5.21 (m, 1H, 1-H in indane); 3.09-3.17 (m, 1H, 3- or 3′-H in indane); 2.85-2.92 (m, 1H, 3′- or 3-H in indane); 2.28-2.37 (m, 1H, 2- or 2′-H in indane); 2.13-2.19 (m, 1H, 2′- or 2-H in indane); 1.20 (s, 6-H, 4,5-Me in BPin); 1.12 (s, 6H, 4′,5′-Me in BPin).