Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Li+].[O:3]=[C:4]1[C:13]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23]([C:43]3[O:47][N:46]=[C:45]([C:48](OCC)=[O:49])[N:44]=3)[CH2:24][C:25]3[CH:33]=[C:32]([CH3:34])[C:31]4[C:27](=[CH:28][N:29]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:30]=4)[CH:26]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1>C(O)C>[O:3]=[C:4]1[C:13]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C@@H:23]([C:43]3[O:47][NH:46][CH:45]([CH2:48][OH:49])[N:44]=3)[CH2:24][C:25]3[CH:33]=[C:32]([CH3:34])[C:31]4[C:27](=[CH:28][N:29]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[N:30]=4)[CH:26]=3)=[O:21])[CH2:18][CH2:19]2)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1
Reactant: CCOC(=O)c1noc([C@@H](Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C2=NC(CO)NO2)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 3 h
Yield: 93.2 %

Procedure:
Solid lithium borohydride (1.5 mg, 0.0689 mmol) was added to a stirred solution of (R)-1-(3-(ethoxycarbonyl)-1,2,4-oxadiazol-5-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethyl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (2.3 mg, 0.00328 mmol) in ethanol (2 mL) at room temperature. The mixture was stirred for 3 h, and then quenched with saturated ammonium chloride and extracted with methylene chloride (15 mL). The organic layer was washed with brine (5 mL), dried over magnesium sulfate, and concentrated in vacuo to afford the expected product (2.02 mg, 94%).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][C@@H:6]([C:8]([O:10]C)=[O:9])[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]2)[CH2:2]1.O[Li].O>C(O)C.O>[C:15]([O:14][C:12]([N:5]1[C@H:6]([C:8]([OH:10])=[O:9])[CH2:7][C:3]2([CH2:2][CH2:1]2)[CH2:4]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)[C@@H]1CC2(CC2)CN1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 102.4 %

Procedure:
To a solution of (S)-5-tert-butyl 6-methyl 5-azaspiro[2.4]heptane-5,6-dicarboxylate (0.436 g, 1.708 mmol) in ethanol (4 mL) was added a solution of LiOH.H2O (86.0 mg, 2.049 mmol, 1.2 eq) in H2O (2 mL) at room temperature. The mixture was stirred at room temperature for 20 hours. EtOH was removed by rotavapor. The aqueous residue was diluted with H2O and extracted with Et2O. The aqueous layer was cooled with an ice bath and acidified to pH ˜2 with 1 N HCl. The resulting milky solution was extracted with a mixed solvent of EtOAc and CH2Cl2. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was dried under vacuum to afford the desired product as an off-white solid (0.422 g, 100%).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-])=O)=[N:13][CH:14]=2)=[CH:6][CH:5]=1)=[O:3]>CCO.CCOC(C)=O.[Pd]>[CH3:1][S:2]([C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CS(=O)c1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)c1ccc(Oc2ccc(N)nc2)cc1
Yield: 53 %

Procedure:
5-(4-Methanesulfinyl-phenoxy)-2-nitro-pyridine (1.27 g, 4.56 mmol) was dissolved in EtOH (30 ml) and EtOAc (8 ml). Pd/C (10%) (400 mg) was added and the nitro group was reduced to the amine by hydrogenation at atmospheric pressure for 3 h. The catalyst was filtered off and the filtrate was evaporated to give 0.6 g of 5-(4-Methanesulfinyl-phenoxy)-pyridin-2-ylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1>CN(C)C=O>[Cl:16][C:17]1[N:22]=[C:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.6 %

Procedure:
2-Amino-N,N-dimethyl-benzenesulfonamide (10.00 g, 49.94 mmol) in N,N-dimethylformamide (200 mL) was treated with sodium hydride 60% dispersion in mineral oil (3.99 g) at 0° C., then 2,4,5-trichloropyrimidine (8.587 mL, 74.90 mmol) was added and the reaction was stirred for 5 minutes at 0° C., then for 3 hours at room temperature. The reaction was quenched with aqueous saturated ammonium chloride, then water. The precipitate was collected by filtration and recrystallized from methanol to give 2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide as a light grey solid (9.3 g, 52%). LC/MS (ESI+): 346.93 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:18]1[CH:26]=[C:25]2[C:21]([C:22]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[N:23][N:24]2[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH:20][CH:19]=1>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:26]=[C:25]3[C:21]([C:22]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[N:23][N:24]3[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)ccc12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(Cl)cc3)ccc12
Temperature: 104 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
512 mg of 4-chlorophenylboronic acid, 578 mg of potassium carbonate, and 167 mg of tetrakis(triphenyl)palladium are added to 900 mg of N-[6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 51, in 40 cm3 of dioxane. The mixture is then heated at about 104° C. for 2 hours and the temperature is allowed to return to about 19° C. over 16 hours. The reaction medium is diluted with 75 cm3 of ethyl acetate, filtered through a sinter funnel packed with Celite and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 100 cm3 of ethyl acetate and 50 cm3 of water. The organic phase is washed again with 25 cm3 of saturated aqueous sodium chloride solution and then separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 600 mg of N-[6-(4-chlorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow wax.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([CH3:17])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:20]N1C(=O)CCC1=O>ClC(Cl)Cl>[Br:20][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH:4]([CH:3]([CH3:17])[C:2]([F:18])([F:19])[F:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(c1ccc(C)cc1)C(C)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(c1ccc(CBr)cc1)C(C)C(F)(F)F

Procedure:
2.25 g (8.2 mmol) of ethyl 4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate, 1.53 g (8.6 mmol) of N-bromosuccinimide and 67 mg (0.41 mmol) of 2,2′-azobis-2-methylpropanenitrile in 36 ml of trichloromethane were stirred under reflux overnight. After the reaction had gone to completion, the succinimide was filtered off, the filter residue was washed with dichloromethane and the filtrate was concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave 2.667 g (7.5 mmol, 92% of theory) of a yellowish oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[F-].[Cs+]>CS(C)=O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: Oc1ccccc1I
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Oc1ccccc1I
Temperature: 50 °C
Yield: 93.5 %

Procedure:
To a solution of 2-iodophenol (11.82 g, 52.7 mmol) and 1-fluoro-2-nitrobenzene (5.0 g, 35.1 mmol) in DMSO (50 mL was added K2CO3 (14.5 g, 105.3 mmol), followed by CsF (8.0 g, 52.7 mmol). The resulting suspension was stirred at 50° C. until no starting material remained (˜5 h), cooled to rt and partitioned between water (50 mL) and CH2Cl2 (50 mL). The water layer was separated and extracted with CH2Cl2 (2×10 mL). The combined organic layers were washed with 1 aq N NaOH (10 mL) and brine, and dried over Na2SO4. Solvent was removed under vacuum to give 1-(2-iodophenoxy)-2-nitrobenzene (11.2 g, 93%) as an oil, which was used for next step without purification.
Reaction SMILES: N#N.[C:3]1([CH2:9][O:10][C:11](=[O:51])[C@@H:12]([CH3:50])[NH:13][C:14](=[O:49])[C@@H:15]([CH2:24][CH2:25][CH2:26][CH:27]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[NH:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[NH:16]C(OC(C)(C)C)=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O>[C:3]1([CH2:9][O:10][C:11](=[O:51])[C@@H:12]([CH3:50])[NH:13][C:14](=[O:49])[C@@H:15]([CH2:24][CH2:25][CH2:26][CH:27]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[NH:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[NH2:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](NC(=O)[C@@H](CCCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)[C@H](N)CCCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Yield: 105.6 %

Procedure:
A solution of 40b (251 mg, 0.37 mmol) in TFA (870 μl) is stirred for 30 min at 0° C. The TFA is removed and the oil is taken up in EtOAc and washed with saturated NaHCO3 solution. Drying and removal of the solvent gives 3b (225 mg, slight excess) which is used in subsequent reactions without further handling: NMR δ 1.39 (d, 3 H) and 1.20-1.70 (overlapping m, 4 H), 1.82 (br s, 2 H), 3.23 (br s, variable, 2 H), 3.33 (br s, 1 H), 4.39 (m, 1 H), 4.47 (apparent quintet, 1 H), 5.03-5.13 (m, 6 H), 5.27 (br d, 1 H), 7.35 (m, 15 H), 7.95 (br d, 1 H) ; MS (FAB) m/z 576 (M+H), 598 (M+Na).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:13](=[O:22])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]1[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:13](=[O:22])[C@H:12]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(=O)[C@H](Cc2ccccc2)C[C@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 0.75 h

Procedure:
A solution of 5(S)-((t-butyl-dimethylsilyloxy)methyl)-N-BOC-2-pyrrolidinone (400 mg, 1.26 mmol) in 2 ml of THF was added to a precooled (-78° C.) 1M solution of lithium hexamethyldisilazide (1.3 ml) in 5 ml of THF. After 45 min, 0.15 ml of benzyl bromide (1.3 mmol) was added and the stirring was continued. After 5 h the reaction was worked up by pouring into a separatory funnel containing 30 ml of an aqueous 10% citric solution. The aqueous layer was extracted (2×30 ml EtOAc) which was backwashed with brine (50 ml) dried, filtered and concentrated to an oil. The residue was chromatographed (SiO2, 20% EtOAc/Hexane) to afford the product as an oil.
Reaction SMILES: [CH3:1][CH:2]([OH:5])[CH2:3][CH3:4].[C:6](Cl)(=[O:14])[O:7][CH2:8][O:9][C:10](=[O:13])[CH2:11][CH3:12]>>[C:6](=[O:14])([O:7][CH2:8][O:9][C:10](=[O:13])[CH2:11][CH3:12])[O:5][CH:2]([CH2:3][CH3:4])[CH3:1]
Reactant: CCC(=O)OCOC(=O)Cl
Reactant: CCC(C)O
Product: CCC(=O)OCOC(=O)OC(C)CC

Procedure:
A mixture of 2-butanol (0.092 mL, 1 mmol), 7c (0.17 g, 1 mmol), and powdered molecular sieve (0.15 g, 4Å) in alcohol-free CHCl3 (2 mL) is refluxed for 18 h. Following filtration through filter-aid and evaporation 0.2 g (98%) of the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:14][CH:13]([NH:15][C:16]3[N:21]=[CH:20][C:19]([C:22]([CH3:24])=[CH2:23])=[CH:18][N:17]=3)[CH2:12]2)[C:3]1=[O:25]>C(O)C.C(OCC)(=O)C.[Pd]>[CH:22]([C:19]1[CH:18]=[N:17][C:16]([NH:15][C@H:13]2[CH2:14][C@H:11]([N:4]3[C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:10]4[C:2]([CH3:1])([CH3:26])[C:3]3=[O:25])[CH2:12]2)=[N:21][CH:20]=1)([CH3:24])[CH3:23]
Reactant: C=C(C)c1cnc(NC2CC(N3C(=O)C(C)(C)c4cccnc43)C2)nc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)c1cnc(N[C@H]2C[C@H](N3C(=O)C(C)(C)c4cccnc43)C2)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Palladium (10 wt. % on activated carbon, 3.53 mg, 3.32 μmol) was added to a mixture of 3,3-dimethyl-1-(−3-((5-(prop-1-en-2-yl)pyrimidin-2-yl)amino)cyclobutyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (example 80, 58 mg, 0.166 mmol) in ethanol (1 mL) and ethyl acetate (0.5 mL) under an argon atmosphere. The reaction mixture was placed under a hydrogen atmosphere (balloon) and stirred at room temperature for 6 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated to yield 1-(trans-3-((5-isopropylpyrimidin-2-yl)amino)cyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one as a yellow solid. M+1: 352.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.85 Hz, 6 H) 1.31 (s, 6 H) 2.23-2.39 (m, 2 H) 2.76 (spt, J=6.94 Hz, 1 H) 3.14-3.26 (m, 2 H) 4.47-4.59 (m, 1 H) 5.16 (quin, J=8.51 Hz, 1 H) 7.08 (dd, J=7.24, 5.28 Hz, 1 H) 7.53 (br. d, J=6.50 Hz, 1 H) 7.76 (dd, J=7.24, 1.57 Hz, 1 H) 8.21 (dd, J=5.28, 1.56 Hz, 1 H) 8.24 (s, 2 H)
Reaction SMILES: I[C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH3:30][Sn](C)(C)C.O>CN(C)C=O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:21][CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: C[Sn](C)(C)C
Reactant: CS(=O)(=O)Oc1ccc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c2ccccc2c(-c2ccc(OS(C)(=O)=O)cc2)c2c1sc1ccccc12
Temperature: 103 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A suspension of methanesulfonic acid 4-(6-iodo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenyl ester (1.65 g, 3.11 mmole), tetramethyltin (3.58, 25.8 mmole), and bis(triphenylphosphine)palladium II chloride (0.218 g, 0.311 mmole 10 mole %) in dry N,N dimethylformamide (16 mL) was heated in a sealed vessel under argon at 103° C. for 4 hours and left at room temperature overnight. The reaction mixture was added to water (200 mL) and extracted with ether. Silica gel (40 mL) was added and the solvent removed. The adsorbate was flash chromatographed (85:15 Petroleum ether:ethyl acetate) to give the title compound as a pale yellow solid (1.12 g, 86%): mp 172-173° C.; NMR (CDCl3); δ 8.18 (ddd, J=8, 1, 1 Hz, 1H), 7.81 (ddd, J=1, 1, 8 Hz, 1H), 7.62-7.55 (m, 3H), 7.50-7.48 (m, 2H), 7.44-7.34 (m, 2H), 7.06 (ddd, J=8, 7, 1 Hz, 1H), 6.64 (ddd, J=8, 1, 1 Hz), 3.32 (s, 3H), 2.99 (s, 3H); MS: EI [m/z] 418 (100%); Anal. Calcd. for C24H18O3S2: C, 68.87, H, 4.34, N, 0.00. Found: C, 68.60, H, 4.26, N, 0.02.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:10]C(=O)OC(C)(C)C)[C:6]([OH:9])([CH3:8])[CH3:7])[CH2:3][CH2:2]1.Cl>C(OCC)(=O)C.O>[NH2:10][C@@H:5]([CH2:4][CH:1]1[CH2:3][CH2:2]1)[C:6]([CH3:8])([OH:9])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(C)(C)O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)[C@@H](N)CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A solution of (S)-tert-butyl 1-cyclopropyl-3-hydroxy-3-methylbutan-2-ylcarbamate (0.8 g, 3 mmol) in ethyl acetate was saturated with hydrochloride (10 mL) and stirred for 1 h at room temperature. After diluting with water (20 mL), the layers were separated and the water phase was washed with ethyl acetate (20 mL). Then it was adjusted with 1 N NaOH to pH=8˜9 and extracted with methylene chloride (3×20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound as yellow oil (0.3 g, 64%); MS (EI): m/e=144.2 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C([Li])CCC.Cl[Si:15]([CH3:18])([CH3:17])[CH3:16]>C1COCC1.CCCCCC>[CH3:16][Si:15]([CH3:18])([CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccccc1[Si](C)(C)C
Temperature: 0 °C
Yield: 4 %

Procedure:
In a 10 ml volume double neck flask substituted with argon gas, was laid 2 ml of a THF solution containing 0.32 mmol/L of o-bromotoluene obtained in the step 2 of Example 1, followed by cooling at 0° C. in an atmosphere of argon gas. To the solution, while stirring using a magnetic stirrer, 0.34 ml of a n-hexane containing 1.58 mol/L of n-butyl lithium was slowly drop wise added and stirred at 0° C. for 30 min. Subsequently, 0.59 ml of a THF solution containing 0.96 mmol/L of chlorotrimethylsilane was slowly drop wise added and stirred at 0° C. for 60 min. After reaction, the resulting solution was analyzed using GC (CBP column 1; 0.25 mm×25 m; starting temperature 50° C.; rate of temperature increase 10° C./min). As a result, o-trimethylsilyltoluene was obtained in yield of 4%. In addition, o-butyltoluene was obtained as a by-product in yield of 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:23]([F:26])([F:25])[F:24])=[C:11]([S:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[I-].[Na+].[CH2:35]([O:37][CH2:38]Cl)[CH3:36]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:38][O:37][CH2:35][CH3:36])[C:10]([C:23]([F:25])([F:24])[F:26])=[C:11]([S:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Sc1ccc(Cl)cc1
Reactant: CCOCCl
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCn1c(-c2ccc(Cl)cc2)c(C#N)c(Sc2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
A mixture of 2-(p-chlorophenyl)-4-[(p-chlorophenyl)thio]-5-(trifluoromethyl)pyrrole-3-carbonitrile (1.7 g, 4.1 mmol), potassium tert-butoxide (0.5 g, 4.5 mmol) and sodium iodide (0.67 g, 4.5 mmol) in tetrahydrofuran is stirred at room temperature for 15 minutes, treated with chloromethyl ethyl ether (0.425 g, 4.5 mmol), stirred at room temperature for 6 hours and poured into water. The aqueous mixture is extracted with diethyl ether. The organic extract is washed sequentially with a 2 molar potassium hydroxide solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an oil. A mixture of the oil in hexanes is stored overnight at room temperature and filtered to obtain the title product as a white solid (1.25 g, mp 98°-100° C.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=[O:5].C1C(=O)N([I:22])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[OH:1][C:2]1[C:9]([I:22])=[CH:8][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C1CCC(=O)N1I
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(OC(F)(F)F)cc(I)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 9.3 %

Procedure:
2-hydroxy-5-(trifluoromethoxy)benzaldehyde (2.0 g, 9.7 mmol) was dissolved into DMF (20 mL) and then added with NIS (5.4 g, 24 mmol) in batches. The mixture was stirred for 2 days at room temperature. At the end of reaction, saturated sodium thiosulfate solution was added and extracted with ethyl acetate, and the organic phase was dried and evaporated in vacuum to obtain the product (0.30 g, 78%) by column chromatography.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].[C:8]([C:10]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)([CH2:13][CH3:14])[CH2:11]Br)#[N:9].O>CS(C)=O>[C:8]([C:10]([C:15]1[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=1)([CH2:13][CH3:14])[CH2:11][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)#[N:9]
Reactant: c1nc[nH]n1
Reactant: CCC(C#N)(CBr)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCC(C#N)(Cn1cncn1)c1ccc(Br)cc1
Reaction time: 1.5 h

Procedure:
2.2 g (0.032 Mol ) of 1,2,4-triazole and 1.3 g (0.032 mol) pulverised NaOH in 30 ml of dimethylsulfoxide are heated at 110°. To this mixture are added, within a few minutes, at 110° a solution of 2-cyano-2-(4-bromophenyl)butylbromide in 10 mol of dimethylsulfoxide. The reaction mixture is stirred at 110° for another 90 minutes, poured into 600 ml of water and extracted several times with diethylether. The united ether phases are washed with water and dried with magnesiumsulfate. Thereafter the ether is evaporated at the water jet and residues of dimethylsulfoxide at high vacuum to give the title compound (solid; m.p. 68°-70°, Rf=0.45 employing CH2Cl2 /CH3OH 95:5 as eluant).
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1)=[O:2].[CH3:12][O:13]/[N:14]=[C:15](/[C:46]1[N:47]=[C:48]([NH:51]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:49][CH:50]=1)\[C:16]([NH:18][CH:19]1[C:44](=[O:45])[N:21]2[C:22]([C:28]([O:30]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:29])=[C:23]([CH2:26]I)[CH2:24][S:25][C@H:20]12)=[O:17].CS(C)=O.C(O)(C(F)(F)F)=O>C(OCC)(=O)C.CCOCC.C1(OC)C=CC=CC=1>[NH2:51][C:48]1[S:49][CH:50]=[C:46](/[C:15](=[N:14]/[O:13][CH3:12])/[C:16]([NH:18][CH:19]2[C:44](=[O:45])[N:21]3[C:22]([C:28]([O-:30])=[O:29])=[C:23]([CH2:26][N+:11]4[C:6]5[CH:7]=[N:8][CH:9]=[CH:10][C:5]=5[S:4][C:3]=4[CH:1]=[O:2])[CH2:24][S:25][C@H:20]23)=[O:17])[N:47]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=Cc1nc2cnccc2s1
Solvent: COc1ccccc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3c(C=O)sc4ccncc43)CS[C@H]12)c1csc(N)n1
Reaction time: 8 h
Yield: 101.1 %

Procedure:
A mixture of 2-formylthiazolo[4,5-c]pyridine (85 mg, 0.5 mmole) and diphenylmethyl 7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIIa] (466 mg, 0.5 mmole) in 5 ml of ethyl acetate containing 2 drops of DMSO was allowed to stand overnight at room temperature and then diluted with ether to give 418 mg of crude quaternary salt. The salt was treated with 3 ml of TFA and 3 drops of anisole at room temperature for 30 minutes. The mixture was concentrated in vacuo and triturated with ether to give 283 mg of powder, which was purified by a column of packing (20 ml) in PrepPAK/C18 cartridge (for Water's System 500) using 200 ml of water and 5% aqueous CH3OH (200 ml) as eluants to give 55 mg (20%) of the title compound Iw. Mp. 135°~139° C. (dec.). Estimated purity by HPLC: 55%.