Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1([CH2:8][OH:9])[CH2:7][O:6]1)([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:7][C@@:5]([OH:6])([C:2]([CH3:4])([CH3:3])[CH3:1])[CH2:8][OH:9]
Reactant: CC(C)(C)C1(CO)CO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)[C@@](C)(O)CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
A solution of 2-(1,1-dimethylethyl)-2-oxiranemethanol (2.3 g, 17.7 mmol) in ethyl ether (10 ml) was added to a suspension of lithium aluminum hydride (1.477 g, 38.9 mmol) in ethyl ether (100 ml) at -5° C. and stirred at room temperature for 30 minutes. The mixture was cooled to 0° C., quenched with 10% aqueous sulfuric acid saturated with sodium sulfate. The aqueous layer was extracted with ethyl acetate and the combined extracts were washed with saturated sodium bicarbonate and brine and dried (magnesium sulfate). Concentration in vacuo followed by recrystallization from hexane gave 1.5 g of (R)-2,3,3-trimethyl-1,2-butanediol as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24](=[CH:30]O)[C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24](=[CH:30][NH:18][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:17][CH:16]=3)[C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(OCCCCN2CCCCC2)cc1
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Product: O=C1Nc2cc(F)ccc2C1=CNc1ccc(OCCCCN2CCCCC2)cc1
Yield: 72.3 %

Procedure:
In a manner similar to that described in Example 231, 4-(4-piperidin-1-yl-butoxy)-phenylamine (400 mg, 1.1 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (263 mg, 1.47 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (435 mg, 73%).
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:13]([O:17][C:18]([NH:20][C:21]1([C:39](O)=[O:40])[CH2:26][CH2:25][N:24]([C:27]2[C:28]3[C:35]([CH:36]4[CH2:38][CH2:37]4)=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([C@@H:2]([NH:1][C:39]([C:21]2([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:22][CH2:23][N:24]([C:27]3[C:28]4[C:35]([CH:36]5[CH2:37][CH2:38]5)=[CH:34][NH:33][C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:25][CH2:26]2)=[O:40])[CH2:3][CH2:4][OH:5])=[CH:11][CH:10]=1
Reactant: N[C@@H](CCO)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]cc(C4CC4)c23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]cc(C4CC4)c23)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
(S)-3-amino-3-(4-chlorophenyl)propan-1-ol (173 mg, 0.93 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 64) (375 mg, 0.93 mmol) and DIPEA (0.489 mL, 2.80 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (391 mg, 1.03 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (75 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Fractions were evaporated to afford (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (420 mg, 79%) as a yellow gum.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[N:6]([C:7]2[S:8][C:9]3[CH2:15][CH2:14][O:13][C:12]4[CH:16]=[C:17]([C:20]5[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]=5)[CH:18]=[CH:19][C:11]=4[C:10]=3[N:33]=2)[C:5](=[O:34])[NH:4][C:3]1=[O:35]>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:36])[N:6]([C:7]2[S:8][C:9]3[CH2:15][CH2:14][O:13][C:12]4[CH:16]=[C:17]([CH:20]5[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:25]5)[CH:18]=[CH:19][C:11]=4[C:10]=3[N:33]=2)[C:5](=[O:34])[NH:4][C:3]1=[O:35]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)OCCc2sc(N4C(=O)NC(=O)C4(C)C)nc2-3)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCCc2sc(N4C(=O)NC(=O)C4(C)C)nc2-3)CC1
Yield: 101.7 %

Procedure:
Tert-butyl 4-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate (48 mg, 0.094 mmol) in 6 ml of ethanol was hydrogenated at 1 atm over 50 mg of 10% palladium on charcoal for 18 hours. The mixture was filtered through celite and concentrated in vacuum giving 49 mg (100%) of tert-butyl 4-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-8-yl)-tetrahydropyridine-1(2H)-carboxylate. MS (ESI+): 513.3
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:27].[Na+].O.OP([O-])(O)=O.[Na+].[NH4+].[Cl-]>CC#N.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:27])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: COc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 25 °C
Yield: 211.8 %

Procedure:
To a solution of 6-chloro-5-(4-methoxy-phenyl)-1H-indole-3-carbaldehyde (27.7 g, 97 mmol) in MeCN (400 mL), tert-butanol (400 mL) and 2-methyl-2-butene (400 mL, 3.76 mol) at 0° C. was added a solution of sodium chlorite (82.0 g, 970 mmol) and sodium phosphate monobasic hydrate (134.0 g, 970 mmol) in water (400 mL) dropwise over 20 minutes. The ice bath was removed and the mixture was stirred at room temperature. At the 16-hour and 20-hour time points, additional 2-methyl-2-butene (200 mL, 1.88 mol) was added, followed by solid sodium chlorite (82.0 g, 970 mmol) and solid sodium phosphate monobasic hydrate (134.0 g, 970 mmol). After a total of 22 hours, the reaction mixture was poured into a solution of saturated NH4Cl (800 mL) and water (200 mL), then extracted with EtOAc (4×500 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo to afford 62 g of a mustard-colored semi-solid. This solid was triturated in CHCl3 (70 mL), filtered and dried under high vacuum to afford 18.5 g pale yellow solid. The solid was stirred in EtOAc (50 mL) overnight at 55° C., then filtered hot and washed with room temperature EtOAc to afford the title compound (19.5 g, 63% for 2 steps) as a pale yellow solid. MS (ES+) 302.5 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 12.10 (br. s., 1H), 11.93 (br. s., 1H), 8.07 (d, J=2.68 Hz, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.35 (d, J=8.54 Hz, 2H), 7.01 (d, J=8.78 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][C:43]1[O:47][C:46]([C:48]([F:51])([F:50])[F:49])=[C:45]([S:52](Cl)(=[O:54])=[O:53])[CH:44]=1>C(#N)C>[F:51][C:48]([F:49])([F:50])[C:46]1[O:47][C:43]([CH3:42])=[CH:44][C:45]=1[S:52]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:54])=[O:53]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C(F)(F)F)o1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)c(C(F)(F)F)o1
Yield: 22.8 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0277 g, 0.0600 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 5-methyl-2-trifluoromethyl-3-furansulfonyl chloride (0.0486 g, 0.195 mmol) to obtain 4-(2-trifluoromethyl-5-methyl-3-furansulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0092 g, yield 23%).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:8]=2[C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].Cl.C(N(CCCC)CCCC)CCC>>[CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:8]=2[C:9]=1[C:10](=[O:19])[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.85 g (5.25 mmol) of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran (from example 3) were dissolved in 5.84 g (26.32 mmol) of tri-n-butylamine hydrochloride at 200° C. After 4 h LC-MS indicated the complete consumption of the starting material and the reaction mixture was cooled to room temperature. After addition of 20 ml of water and 50 ml MTBE the phases were separated, the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water, dried over MgSO4 and evaporated. Flash chromatography gave the title compound which crystallized to yield 1.50 g (83%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH2:29]([S:31]SCC)[CH3:30]>O1CCCC1>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([S:31][CH2:29][CH3:30])[CH:3]=[C:4]2[CH2:10][CH2:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Reactant: CCSSCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCSc1cnc2c(c1)CCN2[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
To a solution 5-bromo-1-(tert-butyl-dimethyl-silanyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 7, 3.3 g, 10.5 mmol) in anhydrous tetrahydrofuran (50 mL) at −78° C. was added a solution of n-butyllithium in n-hexane (1.6M, 10 mL, 16 mmol) dropwise. After stirring for 20 min at −78° C., ethyl disulfide (1.96 g, 16 mmol) was added. The resulting mixture was stirred for 1 h, quenched with a saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (2×100 mL), dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by flash column chromatography (Qingdao silica gel, 300 mesh, 10% dichloromethane/hexanes) to afford 1-(tert-butyl-dimethyl-silanyl)-5-ethylsulfanyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (2.2 g, 71%): LC/MS m/e calcd for C15H26N2SSi [M+H]+ 295.54.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH:33]1([CH2:38][CH2:39][C:40](Cl)=[O:41])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:40](=[O:41])[CH2:39][CH2:38][CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: O=C(Cl)CCC1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)CCC5CCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 44.4 %

Procedure:
Following General Procedure G, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 3-cyclopentyl propionyl chloride (39 mL, 0.690 mmol) gave 7-cyclopentyl-2-{5-[4-(3-cyclopentyl-propionyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (57 mg, 44%). MS (ESI) m/z 559.4 (M+H)+
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][NH:9]2)[CH2:2][CH3:3].[F:14][C@@H:15]1[C@@H:19]([CH2:20][OH:21])[O:18][C@@H:17](N2C=CC(=O)NC2=O)[CH2:16]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[F:14][C@@H:15]1[C@@H:19]([CH2:20][OH:21])[O:18][C@@H:17]([N:9]2[CH:8]=[N:7][C:6]3[C:10]2=[N:11][CH:12]=[N:13][C:5]=3[S:4][CH2:1][CH2:2][CH3:3])[CH2:16]1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCCSc1ncnc2[nH]cnc12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCSc1ncnc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 96 h
Yield: 39.3 %

Procedure:
6-Propylthio-9H-purine (0.50 g, 2.6 mmoles) (Alfred Bader Division of Aldrich Chemical Company) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 500 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 4 days, 175 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (9:1). The product was then further chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (98:2). Solvent was removed and lyophilization yielded 0.27 g of 9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-propylthio-9H-purine (39%): mp 85°-86° C.; TLC Rf 0.87 (silica gel, MeCN:15N NH4OH:H2O/85:5:10); [α]D20 -20.2° (c=0.5, DMF): UV λmax (ε×103-) at pH 7, 293 (20.0); at pH 13, 292 (20.4); 1H NMR (300 MHz, DMSO-d6) δ8.74 and 8.68 (2s, 2H, H2 and H8), 6.48 (dd, 1H, H1', J=9.0 Hz, J=5.8 Hz), 5.46 (dd, 1H, H3', J=53.4 Hz, J=4.2 Hz), 5.21 (t, 1H, OH5', J=5.6 Hz), 4.26 (dt, 1H, H4', J=26.2 Hz, J=4.8 Hz), 3.59-3.62 (m, 2H, H5' and H5"), 3.25 (b, 2H, SCH2CH2CH3), 2.95-3.20 and 2.62-2.80 (2m, 2H, H2' and H2"), 1.69-1.76 (m, 2H, SCH2CH2CH3) and 1.00 (t, 3H, SCH2CH2CH3, J=7.4 Hz); MS (ci) 313 (M+1), 293 (M-F), 195 (MH2 --C5H8FO2).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][CH:34]([CH3:46])[CH2:35][CH2:36][O:37][C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[CH:34]([CH3:46])[CH2:35][CH2:36][O:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:23])=[CH:24][CH:25]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CC(C)NC(C)CCOC(=O)c1ccccc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)C(C)CCOC(=O)c3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridin-6-yl)benzoic acid and rac-benzoic acid 3-isopropylamino-butyl ester as described for example 1.
Reaction SMILES: CO/C(/C)=C\C(Cl)=O.S1C2C=CC=CC=2N=C1S[S:19][CH:20]1[N:23](/[C:24](=[C:28](\[O:30][CH3:31])/[CH3:29])/[C:25](Cl)=[O:26])[C:22](=[O:32])[CH:21]1[NH:33][C:34](=[O:43])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.[C:51]([OH:55])([CH3:54])([CH3:53])[CH3:52]>C(Cl)Cl>[C:51]([O:55][C:25]([CH:24]1[N:23]2[C:22](=[O:32])[C@@H:21]([NH:33][C:34](=[O:43])[CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:20]2[S:19][CH:29]=[C:28]1[O:30][CH3:31])=[O:26])([CH3:54])([CH3:53])[CH3:52]
Reactant: CO/C(C)=C(/C(=O)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Reactant: CC(C)(C)O
Agent: CO/C(C)=C\C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of 266 mg (0.5 mM) of a crude mixture consisting of 2-[4-benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid chloride and 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid chloride in 5 ml of dry methylene chloride is added dropwise over the course of 15 minutes at 0° C., whilst stirring, to a solution of 0.10 ml of triethylamine in 0.5 ml of dry tert.-butanol and 3 ml of methylene chloride. After a further 15 minutes stirring, the reaction mixture is diluted with methylene chloride, washed with water, with dilute hydrochloric acid and again with water, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 10 g of acid-washed silica gel, using toluene/ethyl acetate (4:1) as the running agent. 7β-Phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid tert.butyl ester is obtained. IR spectrum (in CH2Cl2): characteristic bands at 5.60, 5.77, 5.90 and 8.29μ.
Reaction SMILES: Cl.N[C@H](C)CSC1N=C(C2C=CC=CC=2)NN=1.SC1N=C(C2C=CC=CC=2)NN=1.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(Cl)=NC=2Cl)(=O)C.C([O:62][C@@H:63]1[C@H:67]([O:68]C(=O)C)[C@@H:66]([CH2:72][O:73]C(=O)C)[O:65][C@H:64]1[N:77]1[C:101]2[N:100]=[C:99]([Cl:102])[N:98]=[C:81]([NH:82][C@H:83]([CH3:97])[CH2:84][S:85][C:86]3[N:90]=[C:89]([C:91]4[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=4)[NH:88][N:87]=3)[C:80]=2[N:79]=[CH:78]1)(=O)C.C[O-].[Na+]>CO>[Cl:102][C:99]1[N:98]=[C:81]([NH:82][C@H:83]([CH3:97])[CH2:84][S:85][C:86]2[N:90]=[C:89]([C:91]3[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=3)[NH:88][N:87]=2)[C:80]2[N:79]=[CH:78][N:77]([C:101]=2[N:100]=1)[C@@H:64]1[O:65][C@H:66]([CH2:72][OH:73])[C@@H:67]([OH:68])[C@H:63]1[OH:62]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4n[nH]c(-c5ccccc5)n4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[C@@H](N)CSc1n[nH]c(-c2ccccc2)n1
Agent: C[O-]
Solvent: CO
Product: C[C@H](CSc1n[nH]c(-c2ccccc2)n1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 24 %

Procedure:
The title compound was prepared according to method A as described in Example 1 by reacting 3-[(R)-2-amino-1-propylthio]-5-phenyl-1,2,4-triazole hydrochloride [prepared by a Mitsunobu reaction as described in Example 1 using 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (2.0 g, 11.4 mmol) and 3-mercapto-5-phenyl-1,2,4-triazole (2.0 g, 11 mmol) followed by acidic hydrolysis] (0.50 g, 1.8 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (0.75 g, 1.7 mmol), followed by deacylation of the purified 2',3',5'-tri-O-acetyl-2-chloro-N-{(R)-1-[5-phenyl-(1,2,4-triazol-3-yl)]thio-2-propyl}adenosine using sodium methoxide in methanol to provide the title 2-chloro-N-{(R)-1-[5-phenyl-(1,2,4-triazol-3-yl)]thio-2-propyl}adenosine (0.21 g, 24%) as a foam after column chromatography. 1H NMR (DMSO-d6) δ1.34 (3H, d, --CHCH3), 3.37-3.70 (4H, m, --CH2 --, H-5'a and H-5'b), 3.95 (1H, q, H-4), 4.13 (1H, t, H-3'), 4.53 (1H, t, H-2'), 4.59-4.69 (1H, m, --CHCH3), 5.07 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'-and 3'-OH), 5.83 (1H, d, H-1'), 7.43-7.54 (3H, m, Ar--H), 7.90, 8.0 (2H, m, Ar--H), 8.40 (1H, s, H-2). 8.42 (1H, d, --NH), HPLC retention time 14.5 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[Cl:17][CH:18](Cl)[CH3:19]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[CH2:19][CH2:18][Cl:17])=[C:4]([F:11])[CH:3]=1
Reactant: CC(Cl)Cl
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCl)c1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
A solution of 4-Bromo-2-fluoro-benzoyl chloride (26.79 g, 113 mmol) in dichloroethane was added to a stirred suspension of aluminum chloride (15 g, 113 mmol)in dichloroethane at room temperature. The suspension turned into a dark solution after adding the acid chloride. The temperature was maintained by an ice-bath. Ethylene gas was bubbled through the reaction mixture for 3 hours until the acid chloride was consumed. The reaction mixture was stirred over night at room temperature. The reaction mixture was cooled to 0° C. and quenched with a 4 M hydrochloric acid solution (34 ml, 134 mmol). The organic phase was separated and the water phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium bicarbonate solution and brine, dried over sodium sulfate and filtered. After concentrating under reduced pressure, crude 1-(4-Bromo-2-fluoro-phenyl)-3-chloro-propan-1-one (27.45 g, 103 mmol) was obtained which was carried over to the next step.
Reaction SMILES: C([O:14][C:15]([CH2:17][C:18]([NH:20][C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:28]=1[C:29]1[S:33][C:32]([NH:34][C:35](=[O:57])[CH2:36][NH:37]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:31][CH:30]=1)[CH:24]([S:58][C:59]1[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=1)[C:23]2=[O:67])=[O:19])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[C:15]([CH2:17][C:18]([NH:20][C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:28]=1[C:29]1[S:33][C:32]([NH:34][C:35](=[O:57])[CH2:36][NH2:37])=[N:31][CH:30]=1)[CH:24]([S:58][C:59]1[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=1)[C:23]2=[O:67])=[O:19])([OH:16])=[O:14]
Reactant: O=C(CC(=O)OC(c1ccccc1)c1ccccc1)NC1=C(c2cnc(NC(=O)CNC(c3ccccc3)(c3ccccc3)c3ccccc3)s2)CSC2C(Sc3ccc(Cl)c(Cl)c3)C(=O)N12
Solvent: O=CO
Product: NCC(=O)Nc1ncc(C2=C(NC(=O)CC(=O)O)N3C(=O)C(Sc4ccc(Cl)c(Cl)c4)C3SC2)s1
Yield: 48.9 %

Procedure:
2-Benzhydryloxycarbonyl-7-(3,4-dichlorophenylthio)-acetamido-8-oxo-3-(2-tritylaminoacetamido-thiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.61 g) is treated with formic acid (30 cc) and distilled water (3 cc) at 50° C. for 30 minutes and then concentrated to dryness under reduced pressure (2 mm Hg; 0.27 kPa) at 40° C. The residue is treated in accordance with the working method described in Example 24, to give 2-carboxy-7-(3,4-dichlorophenylthio)-acetamido-3-(2-glycylamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.46 g) in the form of a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:3]=1[NH:16][C:17](=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)(=O)C.C1COCC1>[F:15][C:12]([F:13])([F:14])[C:5]1[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]2[NH:1][C:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:16][C:3]=2[CH:4]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nc2cc(C(F)(F)F)cc(C(F)(F)F)c2[nH]1
Yield: 81.8 %

Procedure:
A solution of ethyl 3-(2-amino-3,5-bis(trifluoromethyl)phenylamino)-3-oxopropanoate (330 mg, 0.92 mmol) in 3:1 acetic acid/THF (4 mL) was heated at reflux for 18 h. The mixture was concentrated in-vacuo, and the residue was purified over silica gel, eluting with 20%-30%-40% EtOAc/heptane, to yield 256 mg of a colorless oil as product. 1H NMR (500 MHz, DMSO) δ ppm 1.20 (m, 3 H) 4.11 (m, 4 H) 7.82 (m, 1 H) 8.28 (m, 1 H) 13.37 (m, 1 H).