Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[N+](C1C=CC([O:37][C:38](=O)[NH:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH:47]([CH3:49])[CH3:48])=[CH:42][CH:41]=2)=CC=1)([O-])=O>CO>[CH:47]([O:46][C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:38]([N:16]2[CH2:17][CH2:18][CH:13]([C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=[CH:9][N:8]=3)[CH2:14][CH2:15]2)=[O:37])=[CH:41][CH:42]=1)([CH3:49])[CH3:48]
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: COc1ccc2c(C3CCNCC3)ncnc2c1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(C3CCN(C(=O)Nc4ccc(OC(C)C)cc4)CC3)ncnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Solid KOH (224 mg, 4 mmol) was added to a solution of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (29a; 41 mg, 0.1 mmol), prepared as described in Example 29, in anhydrous MeOH (1 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and concentrated in vacuo. The residue was dissolved in DCM and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain crude 4-(7-methoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (31a). This was dissolved in 2 mL of 3M HCl/MeOH was stirred at rt for 1 h and then concentrated in vacuo to obtain crude 4-(7-methoxy-quinazolin-4-yl)-piperidine (31b) as a di-HCl salt. To a suspension of (31b) in anhydrous MeOH (2 mL), was added DIEA (45 μL, 0.25 mmol) followed by (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (48 mg, 0.15 mmol), as prepared in Example 1a, and the mixture was stirred at rt for 1 h. It was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 1% MeOH/DCM) to obtain 5.4 mg (13% overall yield from 29a) of pure 4-(7-methoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide. 1H-NMR (300 MHz, CDCl3): δ 9.14 (s, 1H), 8.06 (d, 1H), 7.35 (d, 1H), 7.30-7.25 (m, 3H), 6.84 (d, 2H), 6.30 (s, 1H), 4.48 (m, 1H), 4.26 (m, 2H), 3.99 (s, 3H), 3.69 (m, 1H), 3.14 (m, 2H), 2.23-2.05 (m, 2H), 2.03-1.92 (m, 2H), 1.31 (d, 6H). LC/MS (ESI): calcd mass 420.2, found 421.4 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13].[C:20](#[N:23])[CH:21]=[CH2:22].C[O-].[Na+]>CO.ClCCl>[C:20]([CH2:21][CH2:22][C:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])#[N:23]
Reactant: C=CC#N
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(CCC#N)(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Reaction time: 40 h
Yield: 52.4 %

Procedure:
To a solution of the nitro diester, Dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (86) (0.4 g, 1.47 mmol) and acrylonitrile (0.11 mL, 1.62 mmol) in absolute methanol (5 mL) was added a catalytic amount of sodium methoxide at 21° C. under argon. The reaction mixture was stirred for 40 h at the same temperature and then diluted with dichloromethane (50 mL). The resulting mixture was washed with water, brine and dried. The residue obtained upon evaporation of the solvents was purified on a silica gel (hexane:ethyl acetate, 8:1) to give Dimethyl 2-(2-cyanoethyl)-2-(2-fluoro-4-nitrophenyl)malonate (73) (0.25 g, 52%): 1H NMR δ 8.07 (dd, 1H, J=8.7, 2.3 Hz), 7.99 (dd, 1H, J=10.9, 2.3 Hz), 7.47 (dd, 1H, J=8.7, 7.3 Hz), 3.85 (s, 6H), 2.65-2.70 (m, 2H), 2.47-2.51 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Mg].II.[CH3:12][O:13][C:14](=[O:28])[C@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C1COCC1>[CH3:12][O:13][C:14](=[O:28])[C@H:15]([NH:16][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:18][C:17]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1)=[O:20]
Reactant: Fc1cccc(Br)c1
Reactant: COC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CCC(=O)c1cccc(F)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a mixture of 1-bromo-3-fluorobenzene (0.79 g, 4.5 mmol) and magnesium turnings (0.12 g, 5.0 mmol) in anhydrous THF (8 mL) was added a small piece of iodine. The mixture was heated at reflux for 2 hr and no magnesium turnings left. The solution was cooled to 0° C. and transferred into a stirred solution of N-Boc-D-pyroglutamic acid methyl ester (0.80 g, 3.3 mmol) in anhydrous THF (4 mL) at −40° C. under argon atmosphere. After stirring at −40° C. for 1 hr and then at 0° C. for 1 hr, the reaction was quenched with 8 mL of 1:1 HOAc/MeOH and the mixture diluted with Et2O (40 mL). The organic layers were washed with water and brine, dried (Na2SO4) and concentrated under vacuum. Purification by silica gel chromatography (10–20% EtOAc/hexanes) gave 0.57 g (51%) of (2R)-2-tert-butoxycarbonylamino-5-(3-fluoro-phenyl)-5-oxo-pentanoic acid methyl ester as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.82 (1H, d), 7.75 (1H, d), 7.56 (1H, q), 7.38 (1H, t), 5.30 (1H, br.d), 4.50 (1H, br.s), 3.87 (3H, s), 3.20 (2H, m), 2.45 (1H, m), 2.20 (1H, m), 1.54 (9H, s).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[N:15]=[CH:14][N:13]=1.N1C=CC=CC=1>O>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[N:15]=[CH:14][N:13]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
75 μl of methanesulfonyl chloride was added to a mixture comprising 100 mg of 4-(3-amino-4-chlorobenzyl)amino-6-chloroquinazoline and 3 ml of pyridine. The obtained mixture was stirred at room temperature for 1.5 hours. 20 ml of water was added in portions to the reaction mixture to precipitate crystals. The crystals were recovered by filtration, washed with water and dried to give 109 mg of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>O1CCCC1>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: BrCCCCc1ccco1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of furan (23.8 g, 0.35 mol) in dry tetrahydrofuran (150 ml) was cooled to -15° C. A solution of n-butyl-lithium in hexane (150 ml, 2.2 M, 0.33 mol) was then added dropwise under nitrogen and the reaction mixture was then stirred for a further 21/2 hours at 0° C. The solution thus obtained was subsequently added over a period of about 1 hour under nitrogen to a solution of 1,4-dibromobutane (150 g, 0.7 mol) in dry tetrahydrofuran (225 ml) at -25° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[C:6]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[S:8][N:7]=1>C(#N)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]2[S:8][N:7]=[C:6]([NH:3][CH2:2][CH2:1][NH2:4])[C:10]=2[CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc2snc(Cl)c2c1
Reactant: NCCN
Solvent: CC#N
Product: NCCNc1nsc2ccc([N+](=O)[O-])cc12
Yield: 35 %

Procedure:
Ethylenediamine (1.5 mL, 24 mmol) was added dropwise to a solution of 3-chloro-5-nitrobenzo[d]isothiazole (250 mg, 1.2 mmol) in acetonitrile (1 mL). The reaction mixture was microwaved at 120° C. for 10 min. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water and the aqueous mixture was extracted with ethyl acetate. The organic extract was concentrated under reduced pressure and the crude product was purified by column chromatography, on silica gel, eluting with a mixture of 2% methanol in dichloromethane and selected fractions were combined and concentrated under reduced pressure to yield N1-(5-nitrobenzo[d]isothiazol-3-yl)ethane-1,2-diamine (100 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:32]([N:29]([CH2:28][C:5]1[C:4]([CH:1]([OH:3])[CH3:2])=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:12]2[C:7](=[CH:8][C:9]([O:26][CH3:27])=[C:10]([O:24][CH3:25])[CH:11]=2)[N:6]=1)[CH2:30][CH3:31])[CH3:33]
Reactant: CCN(CC)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(C)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
3-Acetyl-2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (0.5 g) was added to an ice-cooled suspension of lithium aluminum hydride (0.045 g) in tetrahydrofuran (10 ml). The mixture was stirred at room temperature for 20 minutes. Then, water (0.3 ml) was added, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethanol (20:1, v/v) gave 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-3-(1-hydroxyethyl)-6,7-dimethoxyquinoline (0.23 g, 45%). This compound was recrystallized from ethyl acetate-hexane to give colorless prisms, mp. 144°-145° C.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]([CH3:22])[C:12](=[O:23])[CH2:11]1>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:22])[C:12](=[O:23])[CH2:11][CH:10]2[CH2:9][CH:8]=[O:7]
Reactant: COc1ccc2c(c1)C(CCO)CC(=O)N2C
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)C(CC=O)CC(=O)N2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled (0° C.) solution of 69 ml of pyridine in 600 ml of dichloromethane was added 42.5 g of chromium trioxide. The resulting mixture was stirred at room temperature for 0.5 hour and a solution of 10.0 g of 3,4-dihydro-4-(2-hydroxyethyl)-6-methoxy-1-methyl-2(1H)-quinolinone in 100 ml of dichloromethane was added, dropwise. The reaction mixture was stirred for 0.5 hour, the solvent was decanted, and the resulting residue washed with dichloromethane. The combined organic layers were washed with 5% sodium hydroxide solution, 10% hydrochloric acid solution, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting oil was filtered through silica (elution with ethyl acetate) and concentrated to afford 1,2,3,4-tetrahydro-6-methoxy-1-methyl-2-oxo-4-quinolineacetaldehyde.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C@H:42]2[O:44][CH2:43]2)=[CH:36][C:35]=1[S:45]([CH3:48])(=[O:47])=[O:46])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C(O)C>[CH2:1]([N:8]([CH2:43][C@H:42]([OH:44])[CH2:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:35]([S:45]([CH3:48])(=[O:47])=[O:46])[CH:36]=1)[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1ccc(C2CCC(NCc3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(S(C)(=O)=O)c3)CC2)cc1

Procedure:
This product is obtained by carrying out the procedure as described in Preparation 1.2 above, using ethyl 4-[4-(benzylamino)cyclohexyl]benzoate and 4-benzyloxy-3-methylsulfonyl-1-((2S)-2,3-epoxypropoxy)benzene, described in patent application WO 99/65895, and without adding thereto the hydrochloric acid solution in ethanol. [M+H+]=672.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].C(N(CC)C(C)C)(C)C.Br[CH2:24][CH2:25][CH:26]=[CH2:27]>CN(C)C=O>[CH2:27]([O:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[NH:8][C:7](=[O:12])[CH:6]=1)[CH2:26][CH:25]=[CH2:24]
Reactant: C=CCCBr
Reactant: O=c1cc(O)c2cc(Cl)ccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCOc1cc(=O)[nH]c2ccc(Cl)cc12
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 6-chloro-4-hydroxyquinolin-2(1H)-one (800 mg, 4.09 mmol) and N,N-diisopropylethylamine (1415 μl, 8.18 mmol) in dimethylformamide (13.6 ml) was added 4-bromo-1-butene (415 μl, 4.09 mmol). The solution was heated to 60° C. and stirred for 18 hours. The reaction mixture was purified by column chromatography to provide the title compound.
Reaction SMILES: CS(C)=O.CC(C)([O-])C.[K+].[SH:11][C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.C(O[CH2:25][C:26]1[C:31]([CH3:32])=[C:30]([O:33][CH2:34][CH:35]2[CH2:40][O:39][C:38]([CH3:42])([CH3:41])[O:37][CH2:36]2)[C:29]([CH3:43])=[CH:28][N:27]=1)(=O)C>C1(C)C=CC=CC=1>[CH3:41][C:38]1([CH3:42])[O:39][CH2:40][CH:35]([CH2:34][O:33][C:30]2[C:29]([CH3:43])=[CH:28][N:27]=[C:26]([CH2:25][S:11][C:12]3[NH:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[N:13]=3)[C:31]=2[CH3:32])[CH2:36][O:37]1
Reactant: CC(=O)OCc1ncc(C)c(OCC2COC(C)(C)OC2)c1C
Reactant: Sc1nc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
To a dimethylsulfoxide (10 ml) solution of potassium t-butoxide (262 mg, 2.33 mmol) and 2-mercaptobenzimidazole (349 mg, 2.33 mmol), (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methyl acetate (500 mg, 1.55 mmol) was added and the mixture was stirred in a nitrogen atmosphere at 150° C. for 3 hours and 10 minutes. After cooled to room temperature, the reaction mixture was diluted with toluene and washed with a diluted aqueous sodium hydroxide solution and a saturated saline solution, dried over sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure. The residue was subjected twice to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1) to obtain the title compound (441 mg, 68.8%) as a white foam.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1.[N:26]1([CH2:32][C:33]([OH:35])=[S:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.O>CC(C)=O>[OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13][CH2:14][S:34][C:33](=[O:35])[CH2:32][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:3]1
Reactant: OC(=S)CN1CCCCC1
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCSC(=O)CN4CCCCC4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 3α-hydroxy-21-methylene-5α-pregnane-11,20-dione (350 mg) in acetone (15 ml) was refluxed with piperidinothioacetic acid for 1/2 hour, poured into water and the suspension extracted into ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulphate and evaporated to give title compound (400 mg) as a white foam. [α]D + 50° (c = 0.19 ).
Reaction SMILES: N1C(C)=CC=CC=1C.S([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])(C(F)(F)F)(=O)=O.[F:24][CH2:25][CH2:26][CH2:27]O>C(Cl)Cl>[F:24][CH2:25][CH2:26][CH2:27][O:16][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:18])=[O:19]
Reactant: OCCCF
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=S(=O)(OCCCF)C(F)(F)F
Temperature: 25 °C

Procedure:
To a cold (−25° C.), stirred solution of 2,6-lutidine (4.60 mL, 39.5 mmol) in DCM (30 mL) was added triflic anhydride (6.00 mL, 35.5 mmol) over 3 min. Then 3-fluoropropane-1-ol (1.61 g, 20.6 mmol) was added. The reaction mixture was warmed to room temperature for 2.5 h. The reaction mixture was then concentrated to half its volume and purified by flash chromatography (Teledyne ISCO CombiFlash, isocratic DCM, REDISEP® SiO2 120 g, detecting at 254 nM, and monitoring at 220 nM). Concentration of the appropriate fractions provided Intermediate S-3A (2.92 g, 67.4%). 1H NMR (400 MHz, chloroform-d) δ ppm 4.69 (2 H, t, J=6.16 Hz), 4.65 (1 H, t, J=5.50 Hz), 4.54 (1 H, t, J=5.61 Hz), 2.25 (1 H, dt, J=11.39, 5.86 Hz), 2.19 (1 H, dt, J=11.44, 5.94 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH2:7][C:6]=2[CH:11]=1.[NH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]([NH2:12])=[O:9])[C:5]2[O:9][C:8](=[O:10])[CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:11]=3)[C:6]=2[CH:11]=1
Reactant: O=C1Cc2cc(Cl)ccc2O1
Reactant: N
Product: NC(=O)Cc1cc(Cl)cc2c1OC(=O)C2c1ccccc1

Procedure:
This compound was prepared according to the process described in Example 6, but using 5-chloro-2,3-dihydro-2-benzofuranone and ammonia solution in Stage A.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C@H:3]1[O:8][C:7](=[O:9])[C@@H:6]([CH3:10])[C@@H:5]([CH3:11])[O:4]1.S(=O)(=O)(O)O.[CH3:19]C(O)C>O>[CH3:10][C@@H:6]([C@H:5]([OH:4])[CH3:11])[C:7]([O:8][CH:3]([CH3:19])[CH3:2])=[O:9]
Reactant: CC(C)O
Reactant: C[C@@H]1C(=O)O[C@H](C(Cl)(Cl)Cl)O[C@@H]1C
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)[C@@H](C)[C@@H](C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TO 1.0 g of (2R, 5S, 6R)-2-trichloromethyl-5,6-dimethyl-1,3-dioxan -4-one obtained by a procedure similar to Example 1-(4) were added 0.1 ml of concentrated sulfuric acid and 10 ml of 2-propanol, stirred at room temperature for one hour, and 20 ml of water was added followed by ether extraction. The ether phase was dried over anhydrous sodium sulfate and ether was distilled off, and then the residue was subjected to distillation to obtain 0.4 g of isopropyl (2S, 3R)-2-methyl-3-hydroxybutanoate. ##STR41##
Reaction SMILES: [CH2:1]=[C:2]1[C@H:7]([C:8]([O:10]C(C)(C)C)=[O:9])[N:6]2[C:15](=[O:27])[C@@H:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:5]2[S:4][CH2:3]1.Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]=[C:2]1[C@H:7]([C:8]([OH:10])=[O:9])[N:6]2[C:15](=[O:27])[C@@H:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:5]2[S:4][CH2:3]1
Reactant: C=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 60.2 %

Procedure:
A stirred solution of tert-butyl (4R, 6R, 7R) -3-methylene-7-phenylacetamido-cepham-4-carboxylate (0.83 g, purity 93.7%, 2.0 mmol) in dichloromethane (80 ml) was cooled to 0° C. Titanium tetrachloride (0.66 ml, 6.0 mmol) was added in 1 min. After stirring for 4 h at 0° C., the suspension was mixed with a chilled 2M solution of hydrochloric acid in water (40 ml). The organic phase was separated and washed with a 1M solution of hydrochloric acid in water (20 ml), water (20 ml), and brine (20 ml). The organic phase was dried over magnesium sulphate and evaporated to give 0.40 g of (4R,6R,7R)-3-methylene-7-phenylacetamido-cepham-4-carboxylic acid (purity 75%, yield 45.1%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH3:2]
Reactant: CCOc1cccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cccc(COc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)c1
Temperature: 60 °C
Reaction time: 16.5 h
Yield: 15.6 %

Procedure:
To methyl 7-(3-ethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (298 mg) dissolved in THF-methanol (10-5 ml) was added a 2 M aqueous solution of potassium carbonate (0.75 ml), and the resulting mixture was stirred at 60° C. for 16.5 hours. The reaction mixture was treated with 1 N hydrochloric acid to bring the pH to 2. The resulting mixture was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the precipitated crystals were washed with hexane-ethyl acetate to obtain 7-(3-ethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (45 mg) as white crystals. The mother liquor was concentrated under reduced pressure to obtain 7-(3-ethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (340 mg) as a brown oil. This compound was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][Sn:9](Cl)([CH3:11])[CH3:10]>C1COCC1>[F:1][C:2]1[C:7]([Sn:9]([CH3:11])([CH3:10])[CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccccn1
Reactant: C[Sn](C)(C)Cl
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cccnc1F

Procedure:
Metalation of 2-fluoropyridine was performed as described in Estel, Marsais and Queguiner, J. Org. Chem. 53, 2740-2744, 1988. The lithium anion was quenched with 1 eq. of trimethyl tin chloride in THF (1 M) at −78° C. and stirred for 30′, quenched with 1 M sodium bicarbonate and extracted with ethyl acetate. Upon Na2SO4 drying and evaporation under reduced pressure the resulting oil was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:17][OH:18])[CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:17][OH:18])[CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cc(CO)ccc1Nc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(CO)ccc1Nc1ccccc1

Procedure:
((3-Nitro-4-(phenylamino)phenyl)methanol (2.141 g, 0.008766 mol) was dissolved in methanol (40 mL) under a nitrogen atmosphere and 10% palladium on carbon (1:9, palladium:carbon black, 0.500 g) was added. The mixture was stirred under one atmosphere of hydrogen for 3 hours. The reaction was filtered, concentrated and the residue dissolved in ethyl acetate, washed with saturated sodium bicarbonate, dried over magnesium sulfate and concentrated to give a crude product that was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C:6]([CH3:11])([CH2:9][OH:10])[CH2:7][OH:8].C(O[CH:19](OCC)[CH2:20][Cl:21])C>>[Cl:21][CH2:20][CH:19]1[O:10][CH2:9][C:6]([O:5][CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[CH3:1])([CH3:11])[CH2:7][O:8]1
Reactant: CCOC(CCl)OCC
Reactant: Cc1ccccc1COC(C)(CO)CO
Product: Cc1ccccc1COC1(C)COC(CCl)OC1

Procedure:
By the method of Example 39, 2-(2-methylbenzyloxy)-2-methyl-1,3-propanediol was reacted with chloroacetaldehyde diethyl acetal to yield a mixture which was separated by column chromatography. The t-isomer was a liquid b.p. 117° C/0.005 mm Hg; nD25 1.5175. The c-isomer was a solid, m.p. 57°-58° C.