Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[N:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:6]1[C:23]([OH:25])=O.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH:42]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH2:44][CH2:43]1.N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C.O>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[N:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:6]1[C:23]([NH:48][S:45]([CH:42]1[CH2:44][CH2:43]1)(=[O:47])=[O:46])=[O:25]
Reactant: COc1ncccc1-c1c(C(=O)O)n(Cc2ccccc2F)c2ccc(C)nc12
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: O
Product: COc1ncccc1-c1c(C(=O)NS(=O)(=O)C2CC2)n(Cc2ccccc2F)c2ccc(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
1-(2-Fluoro-benzyl)-3-(2-methoxy-pyridin-3-yl)-5-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid B5 (100 mg, 0.25 mmol) was diluted with tetrahydrofuran (3 mL) and to the resulting solution was added carbonyl diimidazole (62 mg, 0.38 mmol). The resulting suspension was heated to reflux and allowed to stir at this temperature for 1 hour. The reaction mixture was cooled to room temperature and cyclopropanesulfonamide (46 mg, 0.38 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (76 mg, 0.5 mmol) was added. The resulting reaction was stirred at room temperature for an additional 14 hours, then concentrated in vacuo. The residue obtained was diluted with ethyl acetate (100 mL) and water (10 mL). The organic layer was separated and the aqueous layer extracted twice more with ethyl acetate (2×20 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo to provide a crude residue which was purified using flash chromatography to provide cyclopropanesulfonic acid [1-(2-fluoro-benzyl)-3-(2-methoxy-pyridin-3-yl)-5-methyl-1H-pyrrolo[3,2-b]pyridine-2-carbonyl]-amide B6 (0.09 g, 72% yield). MS: 495.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([O:10][CH2:11][C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)(O)[CH3:13])([CH3:9])[C:5]([F:8])([F:7])[F:6].C[Si]([N:27]=[N+:28]=[N-:29])(C)C.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:22])[C:4]([O:10][CH2:11][C:12]([N:27]=[N+:28]=[N-:29])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)[CH3:13])([CH3:9])[C:5]([F:8])([F:7])[F:6]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(=O)C(C)(OCC(C)(O)c1cccc(Br)c1)C(F)(F)F
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(OCC(C)(N=[N+]=[N-])c1cccc(Br)c1)C(F)(F)F
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a solution of 2-[2-(3-bromo-phenyl)-2-hydroxy-propoxy]-3,3,3-trifluoro-2-methyl-propionic acid methyl ester (5.1 g, 11.92 mmol) in toluene (50 ml) was added trimethylsilyl azide (3.95 ml, 29.8 mmol) and at 0° C. BF3-Et2O (4.53 ml, 35.8 mmol). The reaction mixture was stirred for 2 days at 25° C. and for another day at 40° C. The reaction was carefully quenched by slow addition of the reaction mixture to a cold aqueous NH4OH solution. The product was extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel (toluene to toluene/EtOAc 10:1) to provide a diastereomeric mixture of the title compound as a light yellow oil: TLC (toluene/EtOAc 10:1): Rf=0.69; HPLC RtH5=1.560 min; 1H NMR (360 MHz, CDCl3): δ 7.65 (s, 1H), 7.48 (d, 1H), 7.41 (d, 1H), 7.27 (t, 1H), 3.87 and 3.85 (s, 3H), 3.76 (m, 2H), 1.78 and 1.75 (s, 3H), 1.65 and 1.61 (s, 3H); ESIMS: 427, 429 [(M+NH4)+].
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]2[NH:7][C:8]([C:14]3[C:23]([F:24])=[CH:22][CH:21]=[C:20]4[C:15]=3[N:16]=[C:17]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]([CH3:25])=[N:19]4)=[CH:9][C:10]=2[C:11](O)=[O:12])[CH2:5][CH2:4]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:27]([NH:26][C:17]1[C:18]([CH3:25])=[N:19][C:20]2[C:15]([N:16]=1)=[C:14]([C:8]1[NH:7][C:6]3[C:3]4([CH2:5][CH2:4]4)[NH:2][C:11](=[O:12])[C:10]=3[CH:9]=1)[C:23]([F:24])=[CH:22][CH:21]=2)([CH3:28])([CH3:30])[CH3:29]
Reactant: Cc1nc2ccc(F)c(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(F)c(-c3cc4c([nH]3)C3(CC3)NC4=O)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
To a suspension of 2-(1-aminocyclopropyl)-5-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (295c) (140 mg, 0.32 mmol) in 8 mL of DMF and 8 mL of DCM at RT was sequentially added 1-hydroxybenzotriazole (AK Scientific, Inc., Union City, Calif.) (65 mg, 0.48 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (Sigma-Aldrich) (93 mg, 0.48 mmol) and DIPEA (Sigma-Aldrich) (0.34 mL, 1.94 mmol). The reaction mixture was stirred at RT for 16 h and was then concentrated. The yellow oil was dissolved in CH2Cl2 and washed with water, 1 M NaOH (aq.) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to provide 2′-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (295) (50 mg, 0.13 mmol, 41% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (s, 1H), 7.70 (dd, J=9.00, 5.87 Hz, 1H), 7.63 (s, 1H), 7.30 (dd, J=10.47, 8.90 Hz, 1H), 6.49-6.55 (m, 1H), 6.07 (s, 1H), 2.54 (s, 3H), 1.43 (s, 9H), 1.37-1.41 (m, 2H), 1.29-1.35 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ ppm −111.61 (s, 1F). m/z (ESI, +ve) 380.1 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[NH:3][CH:2]=1.C(Cl)(=O)C([Cl:15])=O>>[Cl:15][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Product: Clc1ncnc2ccccc12

Procedure:
The process for the preparation of Erlotinib disclosed in WO 96/30347 is shown in Scheme-1. The starting material Ethyl-3,4-dihydroxy benzoate of formula (2) is reacted with 2-bromo ethylmethyl ether in presence of a base to obtain bis-O-alkylated compound of formula (3), which is nitrated on ortho position with nitric acid in acetic acid medium to get 2-Nitro-4,5-bis(2-methoxyethoxy)benzo ate of formula (4). The nitro compound of formula (4) on hydrogenation using platinum oxide hydrate gives the amino compound of formula (5), which further reacted with ammonium formate and formamide to get 4-quinazolone compound of formula (6). The 4-quinazolone derivative is reacted with oxalyl chloride to get 4-chloro quinazoline derivative of formula (7), which on condensation with 3-ethynylaniline gives a residue containing Erlotinib base of formula (1). The residue thus obtained is purified by flash chromatography on silica to get Erlotinib base. Then the base is converted to its hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20].Br[CH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.BrCC1CCCCO1>>[CH3:1][C:2]1[SH:3]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20]
Reactant: BrCC1CCOCC1
Reactant: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Product: CC1=Nc2cc3c(cc2[SH]1CC1CCOCC1)C1(CO3)C(=O)Nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 4-(bromomethyl)tetrahydropyran to replace 2-(bromomethyl)tetrahydro-2H-pyran, 2-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one was obtained (44%) as a colorless solid: mp 186-187° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.66-7.60 (m, 1H), 7.34-7.27 (m, 1H), 7.13-7.07 (m, 1H), 7.06-6.91 (m, 3H), 5.04-4.97 (m, 1H), 4.78-4.72 (m, 1H), 4.07-3.93 (m, 3H), 3.52-3.35 (m, 3H), 2.52 (s, 3H), 2.32-2.15 (m, 1H), 2.07-1.95 (m, 1H), 1.91-1.80 (m, 1H), 1.57-1.42 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.4, 169.3, 160.6, 149.2, 143.1, 132.7, 129.1, 128.7, 123.7, 123.0, 122.3, 119.9, 108.7, 108.5, 81.5, 67.9, 62.4, 58.1, 46.6, 34.3, 30.9, 20.2, 14.6; MS (ES+) m/z 407.0 (M+1).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:21]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH:18]([CH3:19])[CH3:20])=[O:28])=[CH:25][CH:24]=1
Reactant: CC(C)OC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CC(C)OC(=NC(=O)c1ccc(F)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from isopropyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate and p-fluorobenzoyl chloride, there is obtained isopropyl N-(p-fluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 90°-93° C.;
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B:31](OC(C)C)([O:36]C(C)C)[O:32]C(C)C>C(O)(=O)C>[C:12]([N:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[B:31]([OH:36])[OH:32])=[N:8][N:9]=[N:10]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: OB(O)c1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -25 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
A solution of 5-phenyl-1-trityl-1H-tetrazole (70.0 g, 180.20 mmol, 1.00 equiv) in THF(dried) (560 mL) was placed in a flask that had been purged and maintained with an inert atmosphere of nitrogen. The mixture was cooled to −25° C. Butyllithium was added to quench the trace of water in the reaction mixture until the color of the mixture remained red for at least 5 minutes. Butyllithium (80.0 mL, 2.5 mol/L) was then added dropwise to the mixture over a period of about 40 minutes at a temperature below −25° C. The temperature of the mixture was raised to −5° C., and the mixture was stirred at −5° C. for 3 hours. The mixture was then cooled to −25° C. and triisopropyl borate (50.8 g, 270.11 mmol, 1.50 equiv) was added dropwise. The mixture was warmed to temperature in the range of 25-35° C. and stirred for 2 hours. The mixture was cooled again in the range of 0-5° C., and 3% aqueous acetic acid (470 mL) was slowly added over 30-40 minutes. The mixture was stirred for 30-40 minutes and then filtered. The crude product was washed with water (2×300 mL) and dried over reduced pressure. The crude product was then purified by re-crystallization from EtOAc (1 g/15 ml) to yield 54 g (69%) of the title compound as a white solid. ES m/z: [M+H]+ calcd for C26H21BN4O2 433.1. found 433.1.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH:18]1([CH2:24][CH2:25][CH2:26][C@@H:27]([C:36]2[O:40][N:39]=[C:38]([CH2:41]OS(C3C=CC(C)=CC=3)(=O)=O)[N:37]=2)[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH:18]1([CH2:24][CH2:25][CH2:26][C@@H:27]([C:36]2[O:40][N:39]=[C:38]([CH2:41][C:2]3[NH:1][CH:5]=[CH:4][N:3]=3)[N:37]=2)[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CC(C)(C)OC(=O)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ncc[nH]2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A solution of tert-butyl 1H-imidazole-1-carboxylate (133 mg, 0.79 mmol) in anhydrous tetrahydrofuran (2 ml), cooled to −78° C., treated with n-butyl lithium, 2.5M in hexanes (320 μl, 0.79 mmol) and stirred under a nitrogen atmosphere for 1 hour. A solution of tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5- yl]hexanoate (Preparation 92) (400 mg, 0.79 mmol) in anhydrous tetrahydrofuran (2 ml) was added slowly and the mixture was allowed to warm to room temperature and stirred at this temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was washed once more with water (20 ml), dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a pale yellow oil (307 mg).
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[C:14]([CH:16]([CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)#[N:15].S([O-])(O)(=O)=O.[Na+].C(OCC)C.Cl.[NH2:38][CH:39]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:41]>ClCCl.N1C=CC=CC=1>[C:42]1([C:40](=[O:41])[CH:39]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[NH:38][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([C:14]#[N:15])[CH3:25])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: NC(C(=O)c1ccccc1)c1ccccc1
Reactant: CC(C#N)CCCCCC(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C#N)CCCCCC(=O)NC(C(=O)c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
9 g of 7-cyanooctanoic acid dicyclohexylamine salt is added to a mixture of 28 cm3 of a molar solution of sodium hydrogen sulphate and 60 cm3 of diethyl ether. The mixture is stirred for 15 minutes at 20° C. and the organic phase is then separated. The latter is dried over magnesium sulphate and filtered and the solvent is evaporated off under reduced pressure. The residue is treated with 14.8 g of thionyl chloride and heated to 50° C. for 3 hours. The mixture is concentrated under reduced pressure. The residual oil is dissolved in 6 cm3 of dichloromethane, and the solution obtained is added to a suspension, stirred and cooled to 5° C. of 6 g of 2-amino-1,2-diphenylethanone hydrochloride in 30 cm3 of dichloromethane containing 4.8 g of pyridine. After treatment, the product obtained is chromatographed on a column 2 cm in diameter containing 48 g of silica gel (50 to 200μ). The column is eluted, collecting 100 cm3 fractions, with 1.2 liters of a diisopropyl ether/ethyl acetate (80:20 by volume) mixture. The fractions emerging at between 0.3 and 1.2 liters are concentrated under reduced pressure (0.2 kPa). 5.9 g (67%) of (RS) -1,2-diphenyl-2-(7-cyanooctanamido)ethanone are obtained in the form of an oil, which is used directly in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH:16]2[O:17][CH2:18][CH:19]([OH:20])[CH:15]2[O:14][CH2:13]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:11]([CH3:10])[CH:12]2[CH:16]3[O:17][CH2:18][CH:19]([OH:20])[CH:15]3[O:14][CH2:13]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CNC1COC2C(O)COC12
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(c1nc(Cl)ncc1Cl)C1COC2C(O)COC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (484.9 mg, 2.64 mmol) and 6-(methylamino)hexahydrofuro[3,2-b]furan-3-ol (530.2 mg, 3.33 mmol) in EtOH (30 mL) was added Et3N (566.0 mg, 5.59 mmol). After addition, the reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in a mixture of EtOAc and water (1/1 (v/v), 100 mL) and extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as a pale yellow solid (760.2 mg, 94.0%).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1)[CH3:3].[CH2:14](I)[CH2:15][CH3:16].[H-].[Na+].O>CN(C=O)C>[CH2:14]([O:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3])[CH2:15][CH3:16]
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(C)c1ccc(C(=O)O)cc1
Reaction time: 1 h

Procedure:
Methyl 4-(1-hydroxyethyl)benzoate (2.0 g) dissolved in DMF (30 ml) was mixed with propyl iodide (3.8 g), and then sodium hydride (50% in oil, 0.53 g) was added. After the end of the exothermic reaction, the mixture was stirred for 1 hour and then water was cautiously added. It was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was hydrolyzed by method P-a. This resulted in the product with the molecular weight of 208.26 (C12H16O3); MS (ESI): 209 (M+H+).
Reaction SMILES: [NH2:1][C:2](=[O:25])/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[O:11][CH:10]([C:16]([F:19])([F:18])[F:17])[C:9]([C:20]([O:22]CC)=[O:21])=[CH:8]2.O.[OH-].[Li+].C(O)C>C1COCC1.O>[NH2:1][C:2](=[O:25])/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[O:11][CH:10]([C:16]([F:17])([F:18])[F:19])[C:9]([C:20]([OH:22])=[O:21])=[CH:8]2
Reactant: CCOC(=O)C1=Cc2cc(/C=C/C(N)=O)cc(Cl)c2OC1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)/C=C/c1cc(Cl)c2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 80 °C
Yield: 48.6 %

Procedure:
The product of step 1 was dissolved in 3 mL of THF and treated with a solution of 0.13 g (2.55 mmol) lithium hydroxide hydrate in 3 mL of water. The mixture was treated with 3 mL of ethanol and heated to 80° C. for two hrs. The volatiles were removed, the residue was acidified at 0° C. to pH=1.0 with dilute hydrochloric acid. The product was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. Concentration of the organic fraction afforded 0.169 g (48.6%) of an off-white solid: 1H NMR(DMSO/300 MHz) 7.87(s, 1H), 7.70(d, J=2.1 HZ, 1H), 7.55(d, J=2.1 Hz, 1H), 7.48(d, J=15.9 Hz, 1H), 6.63(d, J=15.9, 1H), 5.96(q, J=6.6 Hz, 1H). MS (ESI+) 348.0 (M+1, 100). MS(ES−) 346.0(M−1, 100). HRMS (ES−) m/z calcd for (M−H; C14H8ClF3NO4): 346.0088, found 346.0078.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[CH2:8][CH2:9]O)=[O:5].FC1C=CC=C(F)C=1C(NC(C1C=CC(Cl)=CC=1)CCO)=O>>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]1[O:5][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[N:6]=1
Reactant: O=C(NC(CCO)c1cccc(C(F)(F)F)c1)c1c(F)cccc1F
Agent: O=C(NC(CCO)c1ccc(Cl)cc1)c1c(F)cccc1F
Product: Fc1cccc(F)c1C1=NC(c2cccc(C(F)(F)F)c2)CCO1
Yield: 71.3 %

Procedure:
The procedure is as for Example 85, but 4 g (11.1 mmol) of N-(2,6-difluorobenzoyl)-3-amino-3-(3-trifluoromethylphenyl)-1-propanol are employed instead of N-(2,6-difluorobenzoyl)-3-amino-3-(4-chlorophenyl)-1-propanol. 2.7 g (71.1%) of 2-(2,6-difluorophenyl)-4-(3-trifluoromethylphenyl)-5,6-dihydro(4H)1,3-oxazine are obtained as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35](CO)[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.O>[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35]([CH2:20][Cl:24])[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: OCc1cc(OCc2ccccc2)c2cc(F)ccc2c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2cc(CCl)cc(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
To a solution of triphenylphosphine (2.8 g, 10.6 mmol) in anhydrous tetrahydrofuran (16 mL) was added carbon tetrachloride (5 mL). After the mixture was stirred at room temperature for 10 minutes, (4-benzyloxy-6-fluoro-naphthalen-2-yl)-methanol (1.5 g, 5.3 mmol) was added as a solid under a nitrogen atmosphere. After being stirred at reflux for 2 hours, the resulting mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL×2). The combined aqueous layers were extracted with ethyl acetate (100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (elution with 5% ethyl acetate in petroleum ether) to afford 1-benzyloxy-3-chloromethyl-7-fluoro-naphthalene (1.4 g, 87.5%) as a white solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)[O:8][C:9]([CH2:11][O:12][N:13]=[CH:14][C:15]2[CH2:16][S:17][C@@H:18]3[CH:38]([NH:39][C:40](=[O:47])[CH2:41][C:42]4[S:43][CH:44]=[CH:45][CH:46]=4)[C:37](=[O:48])[N:19]3[C:20]=2[C:21]([O:23]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:22])=[O:10])C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:9]([CH2:11][O:12][N:13]=[CH:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:38]([NH:39][C:40](=[O:47])[CH2:41][C:42]3[S:43][CH:44]=[CH:45][CH:46]=3)[C:37](=[O:48])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])([OH:10])=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=NOCC(=O)OC(c3ccccc3)c3ccccc3)CS[C@H]12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CON=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 81.9 %

Procedure:
To a solution of diphenylmethyl 3-(diphenylmethoxycarbonylmethoxyiminomethyl)-7-(2-thienylacetamido)-3-cephem-4-carboxylate (187 mg) in methylene chloride (4 ml) are added anisole (0.8 ml) at 0° C., and trifluoroacetic acid (0.8 ml) under argon atmosphere, and the mixture is stirred for 10 minutes at room temperature. After evaporation of the methylene chloride and trifluoroacetic acid, the mixture is treated with ether to give 3-(carboxymethoxyiminomethyl)-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (86 mg). m.p. 158°-163° C. (decomp.).
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].Br[CH2:8][Si:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:10]>O1CCCC1>[C:13]([NH:12][Si:9]([CH3:11])([CH3:10])[CH2:8][CH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: c1cc[cH-]c1
Reactant: CC(C)(C)N[Si](C)(C)CBr
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)N[Si](C)(C)CC1C=CC=C1
Reaction time: 8 h
Yield: 80 %

Procedure:
32.7 ml of a 2.3 M solution (75 mmol) of sodium cyclopentadienide in tetrahydrofurane was added to a solution of 11.4 g (51 mmol) of 2-bromo-1-tertbutylamino-1,1-dimethylsilaethane. The immediate formation of a pinkish solid was observed, the reaction was continued for 8 hours, then it was concentrated to dryness and it was extracted with hexane, the resulting solution was evaporated in order to give a yellow oil, that corresponds to a mixture of isomers (12.5 g, 60 mmol, yield: 80%). 1H-NMR (CDCl3): 6.5-5.75(m,3H), 2.95(m,2H), 1.90(m,2H), 1.20(s,9H), 0.10(s,6H).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.[Cl-].[CH:30]1([CH2:33][Na])[CH2:32][CH2:31]1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:33][CH:30]2[CH2:32][CH2:31]2)[N:10]=[CH:9]1
Reactant: [Na]CC1CC1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Product: c1nc(CCCOCC2CC2)c[nH]1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 10 mmol of cyclopropylmethylsodium chloride are treated as described in Example 5. The title compound is crystallized in the form of hydrogen maleate from ethanol and diethyl ether.