Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10]COC)[C:7]([CH2:14][C:15]([CH3:17])=[CH2:16])=[C:6]([O:18]COC)[CH:5]=1.Cl>CO>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([OH:10])[C:7]2[CH2:14][C:15]([CH3:17])([CH3:16])[O:18][C:6]=2[CH:5]=1)=[O:22]
Reactant: C=C(C)Cc1c(OCOC)cc(C(=O)OC)cc1OCOC
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Yield: 53.9 %

Procedure:
To a solution of 3,5-bis-methoxymethoxy-4-(2-methyl-allyl)-benzoic acid methyl ester (31) (3.6 g, 9.02 mmol) in methanol (5 mL) was added 1.3 mL concentrated aqueous HCl. The reaction mixture was heated to reflux for 1 hr, quenched with H2O (100 mL), extracted with EtOAc (2×100 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 5% EtOAc in hexane to give a pale yellow solid (1.08 g, 54% yield). 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=1.26 Hz, 1 H) 7.00 (d, J=1.01 Hz, 1 H) 5.63 (s, 1 H) 3.89 (s, 3 H) 3.00 (s, 2 H) 1.50 (s, 6 H); LCMS for C12H14O4 m/z 223.10 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:16])([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:17][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH3:15])([CH3:16])[C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(N(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(C(C)(C)C(=O)O)cc1
Yield: 92 %

Procedure:
A mixture of ethyl (4-dimethylaminophenyl)-2,2-dimethylacetate (1.00 g, 4.25 mmol) and sodium hydroxide (0.85 g) in ethanol (20 mL) and water (9 mL) was heated under reflux for 18 hours. The mixture was cooled, acidified with 10% HCl, and washed with ethyl acetate. The aqueous phase was evaporated. The residue was dissolved in aqueous saturated sodium bicarbonate, and extracted with ethyl acetate. The organic phase was dried, filtered and evaporated to give (4-dimethylaminophenyl)-2,2-dimethylacetic acid as a faint red solid (0.81 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[F:19][C@@H:20]1[C@@H:24]([CH2:25][OH:26])[O:23][C@@H:22](N2C=CC(=O)NC2=O)[CH2:21]1.[N-]=[N+]=[N-].[K+]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:22]2[O:23][C@H:24]([CH2:25][OH:26])[C@@H:20]([F:19])[CH2:21]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: Nc1nc(NCc2ccccc2)c2nc[nH]c2n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=[N-]
Product: Nc1nc(NCc2ccccc2)c2ncn([C@H]3C[C@H](F)[C@@H](CO)O3)c2n1
Temperature: 45 °C
Reaction time: 24 h
Yield: 53.3 %

Procedure:
2-Amino-6-benzylamino-9H-purine (0.64 g, 2.7 mmoles) and 2',3'-dideoxy-3'-florouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml 10 mM potassium phosphate buffer containing 0.04% potassium azide. After the pH was adjusted to 7.0, purified purine nucleoside phosphorylase (15,700 I.U.) and thymidine phosphorylase (4,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) were added to the reaction and the suspension was stirred at 45° C. After 24 hours, purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase immobilized onto 10 ml of DEAE-cellulose were added. After an additional two days, 150 ml of methanol was added to the reaction. The reaction was filtered through Celite and the filtrate was applied to an ionic exchange column (AG1-X2, 2.5×10 cm, OH-- form). After eluting the product with methano, fraction were combined and concentrated. The residue was then purified by flash chromatography on silica gel (5×20 cm column) with dichloromethane:methanol (95:5). Solvent was removed and lyophilization yielded 0.42 g of 2-amino-6-benzylamino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-9H-purine (54%): mp 90°-94° C.; [α]D20 -16.2 (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 282 (17.5); at pH13, 282 (17.7); 1H NMR (300 MHz, DMSO-d6) δ7.95 (s, 1H, H8), 7.93 (b, 1H, NH), 7.28 (m, 5H, C6H5), 6.23 (dd, 1H, H1', J=9.4 Hz, J=5.6 Hz), 5.87 (b, 2H, NH2), 5.54 (t, 1H, OH5', J=5.7 Hz), 5.40 (dd, 1H, H3', J=53.7 Hz, J=4.2 Hz), 4.68 (b, 2H, CH2), 4.19 (dt, 1H, H4', J=27.2 Hz, J=4.4 Hz), 3.60 (m, 2H, H5' and H5"), 2.90 and 2.58 (m, 2H, H2' and H2"); MS (ci) 359 (M+1), 339 (M-F), 241 (MH2 --C5H8FO2).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-])=O.[Cl-].[NH4+].O1CCCC1.C(O)C>[Fe].O>[NH2:15][C:6]1[CH:7]=[C:8]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][C:3]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:2]=1[F:1]
Reactant: NS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(S(N)(=O)=O)ccc1Oc1ccc(F)cc1F
Temperature: 95 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
The product from Example 51A (3.24 g, 9.81 mmol), iron (2.74 g, 49.1 mmol), and ammonium chloride (0.787 g, 14.72 mmol) were combined in the solvent mixture of tetrahydrofuran (21.0 mL), ethanol (21.0 mL) and water (7.0 mL) and heated at 95° C. with vigorous stirring for 3 hours. The mixture was cooled and filtered through a plug of Celite to remove solids. The plug was rinsed repeatedly with methanol and tetrahydrofuran. The filtrate was concentrated and the residue partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated to afford the title compound (2.81 g, 95%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:8])[CH3:7].[Cl-].[Al+3].[Cl-].[Cl-].Br[CH:14]([CH3:16])[CH3:15]>C(Cl)(Cl)Cl>[CH:14]([C:4]1[CH:3]=[C:2]([C:6](=[O:8])[CH3:7])[S:1][CH:5]=1)([CH3:16])[CH3:15]
Reactant: CC(=O)c1cccs1
Reactant: CC(C)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(C(C)C)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(Thiophen-2-yl)ethanone (5.4 mL) was added to an ice cold suspension of aluminum chloride (33 g), in dry chloroform (100 mL). 2-Bromopropane (5.2 mL) was then added dropwise over 5 min. The reaction was allowed to warm to RT and stirred overnight. The dark suspension was cautiously poured onto ice and the mixture stirred for 10 min. The layers were separated and the aqueous phase extracted with DCM (100 mL). The combined organic layers were washed with sodium hydroxide solution (2M, 200 mL) and water (200 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 2% ethyl acetate in isohexane. The fractions containing product were combined and evaporated to give the subtitled compound as a light yellow oil. Yield 5.4 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[N:9][C:10]([C:13]([O:15]C)=[O:14])=[CH:11][CH:12]=1.[ClH:17]>>[ClH:17].[ClH:17].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[N:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(-c2ccccn2)cn1
Agent: Cl
Product: O=C(O)c1ccc(-c2ccccn2)cn1

Procedure:
A stirred solution of methyl 2,3′-bipyridine-6′-carboxylate (0.103 g, 0.48 mmol) in 5M aqueous HCl (2.5 mL) is heated at 80° C. for 2 h. The reaction is concentrated under reduced pressure and azeotroped with MeOH to give crude 2,3′-bipyridine-6′-carboxylic acid dihydrochloride which is used in the next step without further purification. m/z=201 [M++H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.BrC1C=CC=CC=1OC.[Mg].CO[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[O:30][CH2:31][C:32]([CH3:35])([CH3:34])[N:33]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[O:30][CH2:31][C:32]([CH3:35])([CH3:34])[N:33]=1
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Reactant: COc1ccccc1[Mg]Br
Agent: COc1ccccc1Br
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccccc1C1=NC(C)(C)CO1
Reaction time: 20 h
Yield: 90 %

Procedure:
2-Methoxyphenylmagnesium bromide, prepared from 2-bromoanisole (22.4 g, 120 mmol) and magnesium (2.9 g, 120 mmol), in dry THF (75 ml) was added dropwise to a stirred solution of 2-(2-methoxyphenyl)-4,4-dimethyl-2-oxazoline (20.4 g, 100 mmol) in dry THF (150 ml) under N2 at 20° C. Stirring of the solution was continued for 20 hours and then the reaction mixture was quenched by the addition of saturated ammonium chloride solution. The resulting mixture was extracted with ether (2×500 ml), dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (ethyl acetate-hexane) to provide title compound as colorless crystals (25.3 g, 90%), mp 129°-131° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]1[CH2:45][O:44][C:13]([CH2:32][O:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)(/[CH:14]=[CH:15]/[C@H:16]2[C@H:23]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[CH2:22][C@H:21]3[C@@H:17]2[CH2:18][C:19](=[O:31])[O:20]3)[O:12]1.C1(C)C=CC=CC=1.C(O)(C)C>O>[CH2:45]1[CH2:11][O:12][C:13]([CH2:32][O:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)(/[CH:14]=[CH:15]/[C@@H:16]2[C@@H:17]3[C@@H:21]([O:20][CH:19]([OH:31])[CH2:18]3)[CH2:22][C@H:23]2[O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[O:44]1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/C3(COc4ccc5ccccc5c4)OCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CC(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: OC1C[C@@H]2[C@@H](/C=C/C3(COc4ccc5ccccc5c4)OCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Reaction time: 0.5 h

Procedure:
Under argon at -70°, 1.5 ml. of a 20% solution of diisobutylaluminum hydride was added to a solution, cooled to -60°, of 150 mg. of (1S,5R,6R,7R)-6-[(E)-3,3-ethylenedioxy-4-(2-naphthyloxy)-1-butenyl]-7-(tetrahydropyran-2-yloxy)-2-oxabicyclo[3,3,0]octan-3-one (prepared according to Example 5[b]) in 15 ml. of absolute toluene. After 30 minutes, the mixture was combined with 0.75 ml. of isopropanol and 0.75 ml. of water and agitated for 30 minutes at 0°, diluted with 150 ml. of methylene chloride, filtered off from the precipitated aluminum compound, and evaporated under vacuum, thus obtaining 146 mg. of the title compound as a colorless oil. IR: 3600, 1630, 1600, 970 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:43][C:44]#[N:45]>C1COCC1>[C:44]([CH2:43][C@@:19]1([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17][C@H:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:15][CH:14]=2)[N:20]1[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])#[N:45]
Reactant: N#CCBr
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@]1(CC#N)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1,2-pyrrolidinedicarboxylate (D34, 45 g) in dry THF (450 mL) previously cooled to −65° C., was added 1M LiHMDS in THF (115 mL) dropwise. The resulting solution was stirred at −35° C. for 30 minutes. Then the mixture was again cooled to −65° C. and bromoacetonitrile (22 mL) dissolved in dry THF (180 mL) was added. The mixture was left stirring for a further 30 min at the same temperature. The reaction was quenched with saturated ammonium chloride solution (675 mL), THF was evaporated in vacuo and the crude mixture was extracted with EtOAc (2×675 mL). The organic layer was evaporated and the crude material was purified by chromatography on silica gel using cyclohexanes and ethyl acetate (8:2) affording the title compound (51.3 g) as a yellow thick oil.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]([C:14](OCC)=[O:15])[CH2:8][CH2:7]1.[BH4-].[Li+].O>C1COCC1>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([CH2:14][OH:15])[CH2:10][CH2:11][C:12]1=[O:13]
Reactant: CCOC(=O)C1CCC(=O)N(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCC(CO)CCN1Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of ethyl 1-[2,4-bis(trifluoromethyl)benzyl]-7-oxoazepane-4-carboxylate (14.8 g) in THF (400 mL) was added lithium borohydride (4.5 g). The reaction mixture was stirred at 50° C. for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (12.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[N:5]([CH3:7])[CH:6]=1.[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCO.C([O-])([O-])=O.[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[N:5]([CH3:7])[CH:6]=2)=[CH:22][CH:21]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)c1cc(Br)cn1C
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cn1C
Temperature: 100 °C
Yield: 96.8 %

Procedure:
A catalytic amount of tetrakis(triphenylphosphine)palladium, Pd(PPh3)4 (0.477 g, 0.413, 0.06 eq) was added to a solution of 4 (1.5 g, 6.88 mmol, 1 eq) and (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (1.57 g, 6.88 mmol, 1.20 eq) in a 9:3:1 combination (13.5 ml) of EtOH, toluene and water in the presence of K2CO3 (2.856 g, 3 eq.) in a 10-20 mL microwave vial containing a magnetic stirrer. The reaction vessel was flushed with nitrogen during each addition. The reaction mixture was sealed in an inert N2 atmosphere and heated with microwave radiation in an EMRYS™ Optimizer Microwave Station (Personal Chemistry) at 100° C. for 12 minutes. After LCMS and TLC analysis revealed completion of the reaction, the cooled reaction mixture was diluted with water (50 mL), extracted with EtOAc (3×40 mL), the filtrates combined, dried over MgSO4 and concentrated under vacuum. The resulting oil was subjected to flash chromatography (n-hexane/EtOAc 9:1) to give 5 (Yield—2.2 g, 97%). IR (FTIR, vmax/cm−1): 3353, 2975, 1696, 1521, 1441, 1366, 1264, 1235, 1209, 1058, 822, 799, 657; 1H-NMR (400 MHz, CDCl3): δ 7.40 (d, 2H, J=8.8 Hz), 7.33 (d, 2H, J=8.8 Hz), 7.16 (d, 1H, J=2.0 Hz), 7.02 (d, 1H, J=2.0), 6.45 (br s, 1H), 3.95 (s, 3H), 3.83 (s, 3H), 1.52 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ 161.7, 152.8, 136.5, 129.5, 125.9, 125.6, 123.7, 123.0, 119.0, 114.6, 80.5, 51.1, 36.9, 28.4; EIMS m/z (+EI) calc. for C18H22N2O4 (M)+ 330.38. found 330.46 (M+H)+
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[N:5]1[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C@H:4]1[S:3]2.[Br-].[Al+3].[Br-].[Br-]>ClCCl>[CH3:1][CH:2]1[CH:15]=[C:6]([C:7]([O:9][CH2:10][C:11]([Cl:12])([Cl:14])[Cl:13])=[O:8])[N:5]2[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C@H:4]2[S:3]1
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3cccs3)[C@H]1S2
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
A solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-{2-(2-thienyl)acetamido}penam-3-carboxylate (1.74 g.) in dried dichloromethane (20 ml.) was dropwise added at -15° C. to a solution of aluminum bromide (2.14 g.) in dried dichloromethane (10 ml.) and the mixture was stirred for 4 hours at room temperature. After the reaction, the reaction mixture was washed in turn with 5% hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water and then dried. After the solvent was distilled off, the residue (powder) was recrystallized from ethanol to give 2,2,2-trichloroethyl 2-methyl-7-{2-(2-thienyl)acetamido}-3-cephem-4-carboxylate (1.46 g.), mp 161° to 162° C. (dec.).
Reaction SMILES: C[O:2]C1C=C2C(C=CC(=O)N2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O.[CH3:45][O:46][C:47]1[CH:56]=[C:55]2[C:50]([CH:51]=C[C:53](=[O:73])[N:54]2[CH2:57][CH2:58][N:59]2[CH2:64][CH2:63][CH:62]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH2:61][CH2:60]2)=[CH:49][CH:48]=1>CN(C)C=O.ClCCl.CO>[CH3:45][O:46][C:47]1[CH:48]=[CH:49][C:50]2[CH2:51][O:73][C:53](=[O:2])[N:54]([CH2:57][CH2:58][N:59]3[CH2:60][CH2:61][CH:62]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH2:63][CH2:64]3)[C:55]=2[CH:56]=1
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)OC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A solution of 7-methoxyquinolin-2(1H)-one (Intermediate 108, 310 mg, 1.8 mmol) in dry N,N-dimethylformamide (5 mL) was treated at 0° C. under stirring with lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 1.9 mL, 1.9 mmol). The mixture was then stirred for 30 minutes at room temperature and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6, 2.03 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (95:5) gave 333 mg (47%) of the product as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[C@H:10]([CH3:18])[NH:11][C:12](=[O:17])[C@H:13]([CH3:16])[NH:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([NH:27][C@H:28]([C:32](O)=[O:33])[CH:29]([CH3:31])[CH3:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>ClCCl>[CH2:1]([O:8][C:9](=[O:19])[C@H:10]([CH3:18])[NH:11][C:12](=[O:17])[C@H:13]([CH3:16])[N:14]([C:32](=[O:33])[C@H:28]([CH:29]([CH3:30])[CH3:31])[NH:27][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1

Procedure:
A mixture of 10.75 g (0.0407 mole) of N-methyl-L-alanyl-L-alanine benzyl ester and 9.73 g (0.0448 mole) of Boc-L-valine in 200 ml of dry dichloromethane was stirred and cooled at -10° C. as 9.97 g (0.0986 mole) of triethylamine was added. After stirring for 15 minutes, 12.55 g (0.0493 mole) of BOP-Cl was added and the reaction was stirred at -5° C. for 22 hours. The reaction was diluted with 100 ml of dichloromethane, washed with 100 ml of 10% potassium bisulfate, washed with 2×75 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, concentrated, and chromatographed on silica gel using 1:1 ether/hexane as the eluent. The product weighed 17.1 g (91% of theory). Its 200 MHz NMR spectrum in chloroform-d was consistent with the proposed structure.
Reaction SMILES: C([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]2Cl)(=O)C.[Cl:18][C:19]1[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].Cl.N>C(#N)C>[Cl:18][C:19]1[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH:22][C:8]1[C:7]2[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Agent: Cl
Agent: N
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
6-Acetoxy-4-chloro-7-methoxyquinazoline (Example 25-5 in WO01/66099; 10.0 g, 39.6 mmole) was suspended in acetonitrile (400 ml) and 3-chloro-2-fluoroaniline (6.05 g, 41.6 mmole) and hydrogen chloride (4.0M solution in 1,4-dioxane) (10.4 ml, 41.6 mmole) were added. The reaction mixture was refluxed for one hour and then allowed to cool to ambient temperature. The resulting precipitate was filtered off, washed with acetonitrile and diethylether to give a white solid. This solid was added in portions to a stirred 1N methanolic ammonia solution (400 ml). The mixture was stirred for two hours and the precipitate filtered, washed with acetonitrile followed by diethylether and dried under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline as a white solid (12.1 g, 95%); 1H NMR Spectrum: (DMSOd6) 3.95 (s, 3H); 7.18 (s, 1H); 7.20-7.25 (m, 1H); 7.39-7.44 (m, 1H); 7.47-7.52 (m, 1H); 7.65 (s, 1H); 8.31 (s, 1H); 9.45 (br.s, 1H); Mass Spectrum: (M+H)+ 320.