Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH:8]([C:20]([OH:22])=O)[CH2:7]1)=[O:5])[CH3:2].O[N:25]=[C:26]([NH2:34])[CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:7][CH:8]([C:20]2[O:22][N:34]=[C:26]([CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:25]=2)[CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[CH2:11]1)=[O:5])[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N(C)CC)C2)cc1
Reactant: NC(CN1CCOCC1)=NO
Product: CCc1ccc(C2CC(c3nc(CN4CCOCC4)no3)CN(C(=O)N(C)CC)C2)cc1

Procedure:
63 mg (0.20 mmol) of 1-[ethyl(methyl)carbamoyl]-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 45A) and 35 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-morpholin-4-ylethanimidamide were reacted according to the General Method 1. Yield: 5 mg (5% of theory)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[NH:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([OH:24])=[O:23].Cl>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([C:20]1[CH:19]=[C:18]([C:22]([OH:24])=[O:23])[NH:17][CH:21]=1)=[O:5]
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: O=C(O)c1ccc[nH]1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
To a 120 mL dichloromethane solution of 2,4,6-trifluorobenzoyl chloride (4.3 g, 0.022 mol) was added AlCl3 (8.8 g, 0.066 mol) under N2 at room temperature. After stirring for 15 min, 1H-pyrrole-2-carboxylic acid (2.4 g, 0.022 mol) was added in small portions over a 10 min period. Stirring continued at room temperature for 1 hr, then the reaction mixture was treated with dropwise addition of ice-water (20 mL) and 1N HCl to adjust pH to 1. After stirring for another 30 min, the reaction mixture was extracted with AcOEt (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (5.8 g, 97% yield). 1H-NMR (500 MHz, CDCl3): δ 12.48 (br.s, 1H), 7.48 (s, 1H), 7.28-7.38 (m, 2H), 6.83 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[NH:7][C:6]=2[CH:14]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][C:28](B(O)O)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1>C1(C)C=CC=CC=1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[C:3]([C:28]2[CH:27]=[C:26]3[C:31](=[CH:30][CH:29]=2)[N:23]([CH3:22])[CH:24]=[CH:25]3)=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[NH:7][C:6]=2[CH:14]=1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: CS(=O)(=O)c1nc2cc(I)c(Cl)cc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1ccc2cc(-c3cc4nc(S(C)(=O)=O)[nH]c4cc3Cl)ccc21
Reaction time: 0.12 h

Procedure:
To a microwave reactor vial was added 6-chloro-5-iodo-2-(methylsulfonyl)-1H-benzimidazole 16-5 (2 g, 5.6 mmol), PdCl2(dppf) (205 mg, 8.4 mmol), K2CO3 (2.32 g 17 mmol), 1-methyl-5-indoleboronic acid (1.47 g, 8.4 mmol) in 20 mL of toluene and 6 mL H2O. The reaction was run in a microwave reactor for 7 min at 130° C. The reaction mixture was diluted with EtOAc (150 mL) and washed three times with 150 mL portions of saturated aqueous ammonium chloride. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Then CH2Cl2 was added and the desired product precipitated out of the solution. The resulting solid was collected by vacuum filtration and washed with copious amounts of CH2Cl2 to yield the title compound 16-6 as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].[CH3:22][O:23][C:24]([C:26]1[CH:27]=[CH:28][C:29](N)=[C:30]2[C:35]=1[N:34]=[CH:33][CH:32]=[CH:31]2)=[O:25]>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:29]1[CH:28]=[CH:27][C:26]([C:24]([O:23][CH3:22])=[O:25])=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(N)c2cccnc12
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccc(C(=O)OC)c3ncccc23)c1=O
Temperature: 126 °C
Reaction time: 0.75 h
Yield: 2.8 %

Procedure:
A mixture of (160 mg, 0.556 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417), 5-aminoquinoline-8-carboxilic acid methyl ester (226 mg, 1.114 mmol) (Preparation 99) and ethanol (8 mL) was introduced in the microwave oven. The mixture was stirred at 126.0° C. during 45 minutes. The solvent was evaporated and the residue purified by column chromatography (silica gel, dichloromethane/methanol 100:1) and preparative HPLC/MS to yield the title compound (7 mg, 3% yield).
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:6]=[C:7]([F:14])[C:8]([CH2:12]Br)=[C:9]([F:11])[CH:10]=1.[Cl-].[Na+]>CS(C)=O>[Br:4][C:5]1[CH:6]=[C:7]([F:14])[C:8]([CH2:12][C:1]#[N:2])=[C:9]([F:11])[CH:10]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)cc(F)c1CBr
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1c(F)cc(Br)cc1F
Reaction time: 3 h
Yield: 51.7 %

Procedure:
To a mixture of potassium cyanide (0.55 g, 8.4 mmol) in dimethyl sulfoxide (10 mL) at 23° C. was slowly added 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (2 g, 7.0 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was poured into saturated aqueous sodium chloride (100 mL) and was extracted with ether (3×100 mL). The combined organic layers were washed with saturated aq sodium chloride (3×50 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. Purification of the residue by flash chromatography (0-100% ethyl acetate/hexanes) afforded the title product (0.84 g, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.04 (s, 2 H) 7.60-7.62 (m, 1 H) 7.62-7.65 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[O:31][N:30]=[C:29]([CH:32]([CH3:34])[CH3:33])[CH:28]=1)=[O:25].[CH3:35][NH2:36].C1COCC1>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14]([NH:36][CH3:35])[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[O:31][N:30]=[C:29]([CH:32]([CH3:34])[CH3:33])[CH:28]=1)=[O:25]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)C)no4)c(F)cc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)C)no4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 20.9 %

Procedure:
Using a procedure analogous to Example A1, 1-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea (0.203 g, 0.421 mmol, 1.00 eq) and 2.00M MeNH2/THF (2.10 ml, 4.21 mmol, 10.00 eq,) were combined to afford 1-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea (41 mg, 21% yield) as a pale yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.67 (brs, 1H), 8.60 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.81 (brq, J=4.0 Hz, 1H), 7.67 9s, 1H), 7.17 (d, J=12.8 Hz, 1H), 5.96 (s, 1H), 3.59 (s, 3H), 2.90 (d, J=4.8 Hz, 3H), 2.89 (septet, J=7.2 Hz, 1H), 2.08 (s, 3H), 1.16 (d, J=7.2 Hz, 6H); MS (ESI) m/z: 466.0 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[C:10]1([C:20](Cl)=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:20]([O:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: OCCN1CCOCC1
Product: O=C(OCCN1CCOCC1)c1cccc2ccccc12
Yield: 94 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that 2-morpholinoethanol was used instead of the triethanolamine, and 1-naphthoyl chloride was used instead of the benzoyl chloride, to give 2-morpholinoethyl 1-naphthalenecarboxylate in a yield of 94%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[C@H:4]2[C:8]([OH:10])=[O:9].C(O)C.[CH2:14]([NH:21][C@@H:22]([CH3:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH2:14]([NH:21][CH:22]([CH3:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[C@H:4]2[C:8]([OH:10])=[O:9]
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Agent: O=C1CCC2C1[C@H]2C(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
To a solution of crude (±) (6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid (11.9 g, 84.9 mmol, assume 100% potency) in 119 mL of 6:1 ethyl acetate:ethanol at reflux is added 18 g (85.1 mmol) of (S)—N-benzyl-α-methylbenzyl-amine. Upon dissolution, the mixture is allowed to cool optionally followed by seeding at 52° C. Upon cooling to room temperature and stirring an additional 13.5 h, the crystals are collected and washed with 6:1 ethyl acetate:ethanol (2×48 mL). Drying in vacuo gave 10.8 g (36%, 77% de) of the resolved salt as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2ncccc2c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2ncccc2c1
Yield: 106.3 %

Procedure:
Following the procedure of Example 1, Step 3, 6-nitroquinoline (2.5 g) and 5% palladium on carbon (0.10 g) in ethanol (40 mL) was hydrogenated to give 6-aminoquinoline (2.2 g). A mixture of 6-aminoquinoline (2.2 g, 15 mmol), t-butylacetyl chloride (2.2 mL, 16 mmol), and pyridine (2.5 mL, 31 mmol) in dichloromethane (40 mL) was then stirred at ambient temperature for 4 h and then extracted with 1 N HCl. The acidic layer was separated and treated with 50% NaOH until basic. The basic phase was extracted with dichloromethane. The combined extracts were dried (MgSO4) and concentrated. The crude material was triturated with hexane and the solid was collected by filtration to provide 3,3-dimethyl-N-quinolin-6-ylbutanamide (3.0 g). MS (ES) m/z 241.1.
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: Sc1ccccc1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Sc1ccccc1

Procedure:
The title compound was prepared as described in General Method 6 from 1.50 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 1.60 mmol of benzenethiol, and 1.60 mmol of piperidine in 30 mL of dichloromethane. The product was triturated with hexane:ether (1:1) to afford a solid. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 58°-60° C.). 1H NMR (DMSO-d6) δ 2.22-2.39 (m, 3 H), 2.62 (m, 1 H), 3.46 (q, 2 H), 6.48 (m, 2 H), 6.98 (m, 3 H), 7.15 (m, 3 H), 7.25 (m, 2 H), 7.46 (m, 5 H).
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]1([C:12]2[O:13][C:14]3[CH:20]=[C:19]([C:21]([N:23]4[CH2:26][CH:25](O)[CH2:24]4)=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.CCN(C(C)C)C(C)C.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C(Cl)Cl.CN(C=O)C>[CH:6]1([C:12]2[O:13][C:14]3[CH:20]=[C:19]([C:21]([N:23]4[CH2:26][CH:25]([N:46]5[CH2:47][CH2:48][N:43]([C:38]6[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=6)[CH2:44][CH2:45]5)[CH2:24]4)=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(c1ccc2nc(C3CCCCC3)oc2c1)N1CC(O)C1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2nc(C3CCCCC3)oc2c1)N1CC(N2CCN(c3ccccn3)CC2)C1
Temperature: 25 °C

Procedure:
Methanesulfonyl chloride (0.152 mL, 1.9 mmol) was added dropwise to a solution of (2-cyclohexyl-benzooxazol-6-yl)-(3-hydroxy-azetidin-1-yl)-methanone (0.48 g, 1.6 mmol) and DIPEA (0.558 mL, 3.2 mmol) in DCM (20 mL) at −40° C. under nitrogen Immediately following the addition, the cooling bath was removed and the mixture slowly warmed to room temperature. The resulting mixture was then washed with water, dried using magnesium sulfate, filtered, and the solvent removed under reduced pressure. The resulting residue was dissolved in acetonitrile (1 mL). DIPEA (0.41 mL, 2.4 mmol) and N-(2-pyridyl)piperazine (1.6 mmol) were added. The resulting mixture was then microwaved at 160° C. for 4 hours. DMF (3 mL) was added to the resulting mixture, which was then purified by reverse phase liquid chromatography. The fractions containing product were diluted with 1N HCl (5 mL) and then lyophilized to yield 2-cyclohexyl-6-{[3-(4-pyridin-2-ylpiperazin-1-yl)azetidin-1-yl]carbonyl}-1,3-benzoxazole as its corresponding hydrochloride salt.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1>C(O)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: c1cc[nH]c1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C1C=C(c2ccc[nH]2)C(=O)c2ccccc21
Yield: 18 %

Procedure:
Using the procedure described in Example 1, starting with 3.16 millimol of 1,4-naphthoquinone, 25 millimol of pyrrole and 3.16 millimol of copper acetate in 50 ml of acetic acid, the product 2-(1H-pyrrol-2-yl)-[1,4]-naphthoquinone was isolated in a yield of 18% after purification by chromatography on a column of silica.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([C:12]1[CH:13]=[C:14]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])([CH3:11])([CH3:10])[CH3:9].C[O-].[Na+].[CH3:32][O:33][CH2:34]CO>>[C:8]([C:12]1[CH:13]=[C:14]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH2:32][O:33][CH3:34])=[O:26])[CH:15]=[C:16]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:17]=1[OH:18])([CH3:9])([CH3:10])[CH3:11]
Reactant: COCCO
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared from 90 g of toluene, 102.4 g of methyl 3-(3,5-di-t-butyl-4-hydroxyphenyl)-propionate, 18.2 g of ethylene glycol monomethyl ether and 0.35 g of sodium methoxide, by a procedure analogous to that of Example 10. Yield 42.2 g. Melting point 62°-64° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#N)=[CH:6][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[CH:4][C:3]=1[CH3:16].[H-].C([Al+]CC(C)C)C(C)C.Cl.C(=O)(O)[O-:29].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[CH:6][C:7]=1[CH:8]=[O:29]
Reactant: O=C([O-])O
Reactant: Cc1cn(-c2cc(C)c(N)c(C#N)c2)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cn(-c2cc(C)c(N)c(C=O)c2)cn1
Temperature: 40 °C
Reaction time: 6 h
Yield: 38 %

Procedure:
To a solution of 2-amino-3-cyano-5-(4-methylimidazol-1-yl)toluene (166 mg) in tetrahydrofuran (2.6 ml) was added 1.5M diisobutylaluminium hydride (1.1 ml) at 0° C. and the mixture was stirred at 40° C. for 6 hours. After the reaction was completed, 10 ml of 3N hydrogen chloride solution was added to the reaction mixture. The whole mixture was stirred for 1 hour. The mixture was bacidified with saturated sodium bicarbonate solution and was extracted with chloroform. The extract was dried with Na2SO4 and solvent was distilled to give 63 mg (38%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:18][CH:17](OS(C3C=CC(OCCCC)=CC=3)(=O)=O)[CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:34]([NH:41][CH:17]1[CH2:16][N:15]([S:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][CH:10]=2)(=[O:13])=[O:14])[CH2:18]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: CCCCOc1ccc(S(=O)(=O)OC2CN(S(=O)(=O)c3ccc(OCCCC)cc3)C2)cc1
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)N2CC(NCc3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 120 h
Yield: 53.4 %

Procedure:
To a solution of 4-Butoxy-benzenesulfonic acid 1-(4-butoxy-benzenesulfonyl)-azetidin-3-yl ester (0.99 g, 2 mmol) in tetrahydrofuran (4 ml) was added benzylamine (0.86 g, 8 mmol) and the mixture was stirred at 100° C. for 5 days. It was then washed with hexanes, and the residue was extracted with ether. The ether solution was evaporated, and the residue was chromatographed (silica gel, ethyl acetate-hexanes/1:1)to give 0.40 g of an amber gum; MS (ES) m/z 375.0 (MH+); HRMS (ES) Calcd. for C20H27N2O3S (MH+): 375.1742, Found: 375.1743.
Reaction SMILES: [Cl-].[Li+].[Cl-].[Al+3].[Cl-].[Cl-].[C:7]1([O:13][CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClC(Cl)C>[CH3:14][O:13][C:7]1[CH:12]=[CH:11][C:10]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:22])=[CH:9][CH:8]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To an agitated mixture of lithium Chloride (3.18 g., 0.075 mole) and aluminium chloride (20 g., 0.15 mole) in dichloroethane cooled to below -10° C. was added anisole (5.41 g.,-0.05 mole) and benzoyl chloride (7.03 g., 0.05 mole) in dichloroethane (10ml). The reaction mixture was held below -10° C. for one hour then allowed to come to room temperature overnight. The 4-methoxybenzophenone produced (9.55 g., 90.1% yield) had a gas chromatograph/mass spectrometer estimated purity of over 95% with 2% ortho isomers.
Reaction SMILES: C(=O)(O)O.[Na].CC(O[CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=O.[Na].[CH:25]([NH:28][N:29]1[C:33]([SH:34])=[N:32][N:31]=[N:30]1)([CH3:27])[CH3:26].[Na].C(=NN1C(S)=NN=N1)(C)C>O>[NH2:18][C@@H:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([OH:23])=[O:22])=[C:11]([CH2:10][S:34][C:33]3[N:29]([NH:28][CH:25]([CH3:27])[CH3:26])[N:30]=[N:31][N:32]=3)[CH2:20][S:19][C@H:14]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)Nn1nnnc1S
Agent: CC(C)=Nn1nnnc1S
Agent: O=C(O)O
Agent: [Na]
Solvent: O
Product: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Yield: 66.1 %

Procedure:
To a solution of sodium hydrogen bicarbonate (1 g, 12 mmol) in water (80 ml) were added 7β-aminocephalosporanic acid (3 g, 11 mmol) and 1-isopropylamino-5-mercapto-1H-tetrazole sodium salt (4 g, 22 mmol). The mixture was treated in a manner similar to that described in Example 6, (a) to give pale brown powder of 7β-amino-3-[(1-isopropylamino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.7 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([OH:14])[C:5]2[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH2:9][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[F:1][C:2]1[CH:13]=[C:12]([O:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH2:9][C:4]=2[CH:3]=1
Reactant: CC1(C)OCc2cc(F)cc(O)c2O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc(F)cc(OCc3ccccc3)c2O1
Yield: 74.1 %

Procedure:
A solution of 6-fluoro-2,2-dimethyl-4H-1,3-benzodioxin-8-ol (21.4 g, 108 mmol) in DMF (200 mL) was treated with cesium carbonate (70.4 g, 216 mmol) and benzyl bromide (14.1 mL, 119 mmol) for 1 h 45 min at rt. Water was added and the resulting aqueous mixture was extracted twice with ethyl acetate. The organic extracts were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethanol. The recovered white crystalline product was rinsed with hexanes providing 6-fluoro-2,2-dimethyl-8-[(phenylmethyl)oxy]-4H-1,3-benzodioxine (23.04 g, 80 mmol, 74% yield). 1H NMR (400 MHz, CDCl3): δ7.43-7.29 (m, 5H), 6.51 (dd, 1H), 6.31 (dd, 1H), 5.15 (s, 2H), 4.80 (s, 2H), 1.59 (s, 6H); GCMS for C17H17FO3: 288 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[C:20](O)=[CH:19][CH:18]=[CH:17][N:16]=1>>[CH3:14][C:15]1[C:20]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: Cc1ncccc1O
Product: Cc1ncccc1OC[C@@H]1CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 55.1 %

Procedure:
An ice-cooled solution of 1-t-butoxycarbonyl-2-(S)-azetidinemethanol (from Example 7b, 0.623 g, 3.33 mmol) was allowed to react with 2-methyl-3-hydroxypyridine (0.399 g, 3.66 mmol) under the conditions of Example 2a to yield the title compound (0.511 g, 55%). MS (DCI/NH3) m/e: 279 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.10 (dd, J=4.4, 1.5 Hz, 1H), 7.15-7.06 (m, 2H), 4.54-4.53 (m, 1H), 4.35-4.34 (m, 1M), 4.07 (dd, J=10.3, 2.6 Hz, 1H), 3.96-3.88 (m, 2H), 2.51 (s, 3H), 2.42-2.31 (m, 2H), 1.40 (s, 9H).