Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[Li]CCCC.[I:14]I>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([I:14])=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1
Reactant: Fc1cccc(F)n1
Reactant: II
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: Fc1ccc(I)c(F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To a mixture of 2,6-difluoropyridine (1.15 g, 10 mmol, 10. eqv) in toluene (300 ml) was added n-BuLi (4.8 ml, 12 mmol, 1.2 eqv) at −78° C. under nitrogen and the mixture was stirred at the same temperature for 4 hrs. Iodine (2.53 g, 10 mmol) was added with the temperature still below −70° C. The mixture was allowed to warm up to RT and quenched with 10 ml water. The organic solvent was removed under vacuum and the product was collected by filtration. Chromatography by silica gel (petroleum ether: EtOAc=50:1 to 5:1) to give 2,6-difluoro-3-iodopyridine as solid (1.49 g, 6.1 mmol, 61% yield) ESI-MS (M+1): 242 calc. for C5H2F2IN 241.
Reaction SMILES: N[C@@](C)(CC(C)CC)CC(O)=O.[NH2:13][C@@:14]([CH3:26])([CH2:19][CH:20]([CH3:25])[CH2:21][CH2:22][CH2:23]C)[CH2:15][C:16]([OH:18])=[O:17].C([N+]([O-])=O)CCCCCCCCC>>[NH2:13][C@@:14]([CH3:26])([CH2:19][CH:20]([CH3:25])[CH2:21][CH2:22][CH3:23])[CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCCC(C)C[C@](C)(N)CC(=O)O
Agent: CCC(C)C[C@](C)(N)CC(=O)O
Agent: CCCCCCCCCC[N+](=O)[O-]
Product: CCCC(C)C[C@](C)(N)CC(=O)O

Procedure:
A procedure similar to that of 3(S)-Amino-3,5-dimethyl-heptanoic acid was used to prepare 3(S)-Amino-3,5-dimethyl-nonanoic acid. m/z 188.1 (C10H21NO2+H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8](O)([CH3:10])[CH3:9]>>[CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])([CH3:10])[CH3:9]
Reactant: Oc1ccccc1
Reactant: CC(C)O
Product: CC(C)c1ccccc1O

Procedure:
In a manner similar to the procedure of Example I, phenol is alkylated with an isopropanol alkylating agent in the presence of an amorphous aluminosilicate alkylation catalyst. Using reaction conditions approximately identical to those of the Example I alklation procedure, an alkylation product containing phenol and isopropylphenol is produced.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8](O)([CH3:10])[CH3:9].C=CC>C(C1C=C(O)C=CC=1)(C)C>[CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])([CH3:10])[CH3:9]
Reactant: CC(C)O
Reactant: Oc1ccccc1
Agent: CC(C)c1cccc(O)c1
Solvent: C=CC
Product: CC(C)c1ccccc1O

Procedure:
Organic compound mixtures enriched in meta-isopropylphenol are prepared by alkylating phenol with isopropanol or propylene to form mixtures of isopropylphenol isomers and by subsequently selectively cracking the para-isopropylphenol isomer from such a mixture over a ZSM-5 type cracking catalyst. Concentration of the para-isomer is thereby selectively reduced relative to the meta-isomer and the meta-isopropylphenol isomer can be further separated from the remaining mixture by fractionation procedures.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].C(#N)C.N(OC(C)(C)C)=O.C(Br)(Br)[Br:39]>>[Br:39][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A suspension of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethanesulphonylpyrazole (43.8 g) was stirred in a mixture of bromoform (141 ml) and dry acetonitrile (63 ml). Tert-butyl nitrite (29.9 g) was added dropwise during 5 minutes, and the mixture heated at 60-70° C. for 2.75 hours. After cooling to 25° C. a further addition of tert-butyl nitrite (29.9 g) was made, and the heating resumed for 2 hours. Evaporation in vacuo gave a yellow oily solid which was triturated with hexane and filtered off. Two recrystallisations from toluene/hexane gave 5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-trifluoromethanesulphonylpyrazole as a yellow solid (34.0 g), m.p. 136-137° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:15]1[O:16][C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)([CH3:9])[O:10][CH2:14]1
Reactant: OCCO
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(c2ccc(O)c([N+](=O)[O-])c2)OCCO1

Procedure:
A solution of 4'-hydroxy-3'-nitroacetophenone (known compound, 12.1 g, 67.0 mmol), benzene (100 ml), ethylene glycol (5.61 ml, 100 mmol) and p-toluenesulfonic acid hydrate (catalytic amount) was refluxed overnight removing the resulting water by azeotropic distillation with benzene. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel to give the object compound (1) as an oil. Yield 14.6 g (97%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[N:23]1[C:28]2[NH:29][C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[NH:32][CH2:33][C:27]=2[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:32]1[C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[NH:29][C:28]2[N:23]=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:33]1)=[O:6]
Reactant: Cn1ccc(-c2ccc(C(=O)O)c(Cl)c2)n1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ccc(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under anhydrous conditions a mixture of the 2-chloro-4-(1-methyl-1H-pyrazol-3-yl)-benzoic acid of Example 13, Step E (1.9 g, 8.05 mmol) and oxalyl chloride (0.79 mL, 9.0 mmol) in 20 mL of dichloromethane containing a catalytic amount of dimethylformamide was stirred at ambient temperature for 1 hour. The solvent was evaporated and the solid acid chloride was dissolved in 5 mL of dimethylformamide and added directly to a mixture of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (1.59 g, 8.05 mmol) and potassium carbonate (1.25 g, 9.0 mmol). After stirring for 2 hours at ambient temperature the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated to small volume. Flash chromatography of the residue (on silica Merck 60, ethyl acetate-hexane, gradient from 4:3 to 2:1) gave the product as a syrup which crystallized from diethyl ether (1.8 g, 61% yield1) as a white solid, m.p. 196-197° C. Another recrystallization from ethanol-diethyl ether provided a higher melting polymorph, m.p. 202° C. as determined by differential scanning calorimetry.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([OH:12])=O)[CH:3]=1.S(Cl)([Cl:15])=O>ClC(Cl)C>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([Cl:15])=[O:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Solvent: CC(Cl)Cl
Product: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)n1

Procedure:
A solution of 4,5,6-trichloropyridine-2-carboxylic acid (5.20 g, 23.1 mmol) and thionyl chloride (3.0 mL) in dichloroethane (30 mL) was refluxed until the evolved gas ceased. The reaction mixture was concentrated to give 4,5,6-trichloropyridine-2-carbonyl chloride (5.60 g, 23.0 mmol), mp 60-62° C.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH:9][CH:10]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11]1.N1C=CN=C1.O>C1COCC1.CN(C=O)C>[Si:5]([O:9][CH:10]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:11]1)([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)C1CCC(O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCC(C(=O)OCc2ccccc2)C1
Reaction time: 3 h
Yield: 101 %

Procedure:
A solution of TBSCl (7.5 g, 50 mmol) in THF (50 mL) was added dropwise to a solution of benzyl 3-hydroxycyclopentanecarboxylate (10.0 g, 45.0 mmol) and imidazole (3.4 g, 50 mmol) in DMF (100 mL) at ambient temperature. The reaction mixture was stirred for 3 h and water (300 mL) was added. The resulting mixture was extracted with EtOAc (200 mL×3). The combined organic extracts were washed with 5% aqueous KHSO4 (100 mL×3), saturated aqueous NaHCO3 (100 mL×3), and brine (100 mL×1), respectively. The organic solution was dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:20) to afford benzyl 3-(tert-butyldimethylsilyloxy)cyclopentanecarboxylate (15.2 g, quantitative) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[CH2:9]([O:11][C:12](=[O:20])[CH:13]([C:17](=O)[CH3:18])[C:14](=O)[CH3:15])[CH3:10].N1C=CC=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[C:14]([CH3:15])=[N:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:17]=1[CH3:18])=[O:20])[CH3:10]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1ccccn1
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2ccccn2)c1C

Procedure:
Similar to Example 1, 2-pyridylhydrazine (7.5 mmol, 0.8 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (7.5 mmol, 1.3 g) were mixed in a solution of 50% pyridine in ethanol, then heated under reflux. The solvents were removed under vacuum and the residue purified over silica. The named product crystallized upon standing (m.p. 49° C.–50° C.).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].CCOCC.C([Li])CCC.[CH3:16][Si:17]([CH3:20])([CH3:19])Cl>CCCCCC.O>[CH3:16][Si:17]([CH3:20])([CH3:19])[C:4]#[C:3][CH2:2][CH2:1][OH:5]
Reactant: C#CCCO
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(C)C#CCCO

Procedure:
A solution of 33.25 parts of 3-butyn-1-ol in 500 parts by volume ether is cooled to -60° C. under argon and treated dropwise with 400 parts by volume of a 2.5 molar solution of n-butyl lithium in hexane. One hour after the addition is complete, a solution of 130 parts by volume of trimethylchlorosilane in 130 parts by volume of ether is added dropwise. After the addition is complete, the temperature is allowed to rise to 0°. The reaction mixture is poured into water, washed with 1NHCl 3 times, additional water, dried over sodium sulfate and evaporated to a liquid which is distilled under water aspirator pressure to give 4-trimethylsilyl-3-butyn-1-ol, bp. 75-77 (13 Tor).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:2]2[CH:14]=[CH:13][C:5]3[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=3[CH:3]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(S)cc1
Reactant: CC1=Cc2cc(Br)ccc2OC1(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Sc2ccc3c(c2)C=C(C)C(C)(C)O3)cc1

Procedure:
6-Bromo-2,2,3-trimethyl-2H-benzo[b]pyran (9.637 g) (see Preparation 4) was dissolved in absolute ethanol (200 ml), then sodium tert-butoxide (11.029 g), 4-methoxybenzenethiol (4.9 ml) and tetrakis(triphenylphosphine)palladium(O) (0.454 g) were added and the mixture was heated under reflux under a nitrogen atmosphere for 48 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulphate), the solvent was removed under reduced pressure and the crude product was chromatographed on silica using 1:1, hexane: dichloromethane as the eluent to yield 6-(4-methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (7.823 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:24]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:33]2[CH2:34][CH2:35][CH:30]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:36])[CH:28]=[CH:27][C:26]=3[CH3:29])[CH2:31][CH2:32]2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(Cc2ccc(Oc3ccc(F)c(F)c3)cc2)CC1

Procedure:
Prepared by Procedure AA and Scheme AJ using 4-(3,4-difluorophenoxy)benzaldehyde and using 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 479.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.Cl>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH:26][CH:23]1[CH2:25][CH2:24]1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: NC1CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
Into a flame-dried 250 mL round-bottom flask equipped with a magnetic stir bar and under N2 were added 5-bromo-2-chlorobenzoic acid (10.0 g, 42.5 mmol) and DMF (3.9 mL, 51.0 mmol) in toluene (80 mL). The sol. was cooled to 0° C., and oxalyl chloride (4.4 mL, 51.0 mmol) was added dropwise over 1 h. The resulting mixture was stirred at 0° C. for 2 h and then the volatiles were removed. The resulting crude reaction mixture was dissolved in CH2Cl2 (100 mL) and cooled to 0° C. in an ice bath. Cyclopropylamine (4.5 mL, 63.7 mmol) was added dropwise over 1 h followed by addition of DIPEA (11.8 mL, 85.0 mmol). The resulting sol. was stirred at rt for 16 h. The reaction mixture was poured into a 1 L separatory funnel containing aq. 1M HCl (600 mL). The mixture was extracted with CH2Cl2 (6×250 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The product was crystallized from hexane/CH2Cl2 and isolated by filtration to give the title compound (8.24 g, 71%).
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1.Cl>O>[CH2:2]([O:9][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCc1ccccc1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: Cl
Agent: [Na]
Solvent: O
Product: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Temperature: 148 °C
Yield: 88.2 %

Procedure:
Sodium (368 mg, 16 mmol) was added to benzyl alcohol (10 ml, 96 mmol) and the mixture was heated at 148° C. for 30 minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (656 mg, 4 mmol), (J. Chem. Soc. section B 1967, 449), was added and the mixture maintained at 148° C. for 24 hours. The reaction mixture was allowed to cool, the solution was poured on to water (170 ml) and the aqueous mixture adjusted to pH3 with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water, ether and dried under vacuum to give 7-benzyloxy-3,4-dihydroquinazolin-4-one (890 mg, 89%) as a white solid. m.p. 267-269° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1.Cl>CC(N(C)C)=O.O>[CH2:1]([O:8][C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
Benzyl alcohol (12.6 ml, 122 mmol) was added dropwise over 15 minutes to a slurry of sodium hydride (60% dispersion in mineral oil, 7.6 g, 190 mmol) in dimethylacetamide (100 ml) cooled in an ice-bath. The mixture was stirred at 0° C. for 15 minutes and then 7-fluoroquinazolin-4(3H)-one (prepared as described in WO03/055491) (10.0 g, 61 mmol) was added portionwise over 15 minutes. The mixture was warmed to room temperature and then heated at 60° C. for 15 hours and then at 80° C. for 3 hours. The mixture was poured into water (600 ml) and made acidic (pH˜6) by the addition of concentrated hydrochloric acid. The resultant precipitate was filtered and washed with water to yield 7-(benzyloxy)quinazolin-4(3H)-one as a colourless solid (11.5 g, 75% yield):
Reaction SMILES: [OH-].[K+:2].[CH2:3]([CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([OH:8])=[O:7])[CH3:4]>O1CCCC1>[CH2:3]([CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([O-:8])=[O:7])[CH3:4].[K+:2]
Reactant: CCCCC(CC)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCC(CC)C(=O)[O-]

Procedure:
Potassium hydroxide (67.3 g) was suspended in tetrahydrofuran (1.2 liters) and to the suspension was added 2-ethylhexanoic acid (173.1 g) was added. The mixture was stirred until potassium hydroxide was dissolved to obtain a solution of potassium 2-ethylhexanoate.
Reaction SMILES: C(Cl)Cl.[CH2:4]([CH:6]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7]([OH:9])=[O:8])[CH3:5].CC(C)([O-])C.[K+:19]>C1COCC1>[CH2:4]([CH:6]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7]([O-:9])=[O:8])[CH3:5].[K+:19]
Reactant: CCCCC(CC)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCC(CC)C(=O)[O-]
Temperature: 0 °C

Procedure:
To a dry flask under N2 atmosphere there was added 37.5 ml. of methylene chloride, 2.5 ml. of THF and 0.88 ml. of 2-ethylhexanoic acid. The solution was cooled to 0° C. and 3.25 ml. of potassium tertbutoxide in THF solution (1.6M of t-BuOK) was added to form in situ the potassium 2-ethylhexanoate salt base. To this mixture there was added 3.10 g. of the 3-hydroxymethyl-cephalosporin reactant, named in Example 1, part D, and 0.122 g. of DMAP and 0.84 ml. of triethylamine, followed by 3 ml. of CH2Cl2 containing 0.485 ml. of α-chloropropionyl chloride. When the addition was complete, a second 0.84 ml. portion of triethylamine and 3 ml. of CH2Cl2 solution containing 0.485 ml. of α-chloropropionyl chloride was added. The resulting reaction mixture was then added to 40 ml. of water containing 5 ml. of 1M sulfuric acid. Then 8 ml. of hexane were added. The reaction mixture was filtered and dried to obtain 2.29 g. of the hereinabove named 3-(α-chloropropionyloxymethyl)-compound. The NMR spectrum for this product was similar to that described in Example 1, but with the 3'-CH2 reading at 4.9(m), the -CHCl at 4.4(q) and the CHCl-CH3 at 1.5(d).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][C:10]2=[O:15])=[O:4]>C(O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][CH:10]2[OH:15])=[O:4]
Reactant: COC(=O)c1cccc2c1SCCC2=O
Solvent: CCO
Product: COC(=O)c1cccc2c1SCCC2O
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Methylthiochroman-4-one-8-carboxylate (0.500 g, 2.25 mmol) was dissolved with stirring in ethanol (20 ml). After 1 h, the reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The aqueous layer was then extracted with ethyl acetate (1×) and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give a yellow oil, which was purified by silica-gel chromatography (1:1 Pentane:EtOAc as eluant) to give the title compound as a colourless oil (0.499 g, 99%)
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][CH:11]([OH:27])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:10][CH:11]([O:27][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccccn1
Reactant: CC(O)COc1ccc(Oc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(COc1ccc(Oc2ccccc2)cc1)Oc1ccccn1
Reaction time: 6 h
Yield: 121.4 %

Procedure:
To a mixture of sodium hydride (0.61 g, 15 mmol; 60% in oil) and 2-chloropyridine (1 g, 9 mmol), there was dropwise added a mixture of 1-methyl-2-(4-phenoxyphenoxy)ethanol (3.0 g, 12 mmol) and 2-chloropyridine (5 g, 44 mmol) with stirring at an inner temperature of 0° to 5° C. Tetra-n-butylammonium bromide (0.2 g) was added to the resultant mixture, and stirring was continued at room temperature for 40 minutes and at an inner temperature of 85° to 90° C. for 6 hours. After allowed to cool, toluene (10 g) was added thereto, and the resultant mixture was washed with water and extracted with 35% hydrochloric acid (7.5 g) twice. To the hydrochloric acid layer, a 10% aqueous sodium hydroxide solution was added to make basic, followed by extraction with toluene (10 g) twice. The toluene extract was washed with a 10% aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution in order and dried over anhydrous magnesium sulfate. Removal of the solvent gave 2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine (3.51 g) as pale brown crystals.
Reaction SMILES: [O:1]([C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:15][CH:14]([O:16][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:13][O:12][C:11]1[CH:17]=[CH:18][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccccn1
Reactant: CC(O)COc1ccc(Oc2ccccc2)cc1
Product: CC(COc1ccc(Oc2ccccc2)cc1)Oc1ccccn1

Procedure:
The resulting oily substance containing 1-(4-phenoxyphenoxy)-2-propanol is reacted with 2-chloropyridine in the same manner as described in Example 9 to give 2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:24].[NH4+]>S(=O)(=O)(O)O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)([C:14]([NH2:15])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: N#CC1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)C1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 24 h

Procedure:
Cautiously combine 1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carbonitrile (60 mmol) and concentrated sulfuric acid (270 mL). Let stand for 24 h at ambient temperature. Cautiously pour the reaction mixture into excess dilute ammonium hydroxide solution/ice. Extract with dichloromethane (3×300 mL). Combine the dichloromethane extracts and extract them using saturated NaHCO3 solution (3×300 mL). Dry the dichloromethane solution over magnesium sulfate, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.