Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([CH:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])C=CC=CC=1.[OH-].[Na+].[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[C:8]1(=[O:16])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:7]1
Reactant: O=C1c2ccccc2CC1c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCc2ccccc21

Procedure:
Racemic 2-phenylindanone VI is the starting material for the process of the invention. As shown in Step B, indanone VI is directly converted to the methylated intermediate VII containing the (+) and (-) enantiomers by treating indanone VI with methyl halide and an aqueous base (e.g., 50% aqueous sodium hydroxide) in an organic solvent (e.g., toluene) in the presence of a chiral catalyst at a temperature, of about 15° C. The 2-methylated (+) and (-) enantiomer of intermediate VII can then be O-demethylated in the presence of a catalyst (AlCl3) to obtain the optically active intermediate (+) and (-) enantiomer indanone mixture VIII which, in turn, can then be alkylated, hydrolyzed, and acidified to obtain the pure (+) and (-) enantiomers of indenyl-oxy acetic acid I at a yield of about 65-80%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1cncc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 3,5-dibromopyridine (1.00 g) in toluene (10 mL) and ethanol (5 mL) was added phenylboronic acid (515 mg), sodium carbonate (1.34 g) and tetrakis (triphenylphosphine)palladium(0) (24 mg) and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted into ethylacetate (2×30 mL). The organic layers were washed with brine (40 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 3-bromo-5-phenyl-pyridine as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].O1CCCC1.[CH3:17][NH:18][CH3:19]>O>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([N:18]([CH3:19])[CH3:17])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(C=O)cc1
Reaction time: 1 h

Procedure:
A mixture of 15.0 g. of 4-carboxybenzaldehyde, 17.0 g. of N,N'-carbonyldiimidazole and 150 ml. of tetrahydrofuran is allowed to stand at room temperature for one hour. Dimethylamine is passed thru the above solution for one hour and the reaction mixture is allowed to stand at room temperature for 18 hours, then is heated at reflux temperature for one hour. Water is added and the solvent is distilled off. The residue is extracted with methylenechloride. The organic layer is washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated to an oil. The oil is triturated with a little methylene chloride and the insoluble material is filtered off. The mother liquor is concentrated and 7.9 g. of p-formyl-N,N-dimethylbenzamide is obtained as an oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[C:13]([NH2:14])=[C:12]([C:15](O)=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O>CN(C=O)C>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[C:13]([NH2:14])=[C:12]([C:15]([NH2:22])=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1c(-c2cccc(C(F)(F)F)c2)nsc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=O)c1snc(-c2cccc(C(F)(F)F)c2)c1N
Temperature: 0 °C
Reaction time: 2.25 h

Procedure:
One gram of 3-(3-trifluoromethylphenyl)-4-amino-5-isothiazolecarboxylic acid and 0.7 g. of carbonyldiimidazole were dissolved in 25 ml. of DMF at ambient temperature. The solution was stirred for 2.25 hours; 3 ml. of 14N aqueous ammonium hydroxide were added and the resulting mixture stirred overnight at ambient temperature after which time it was poured into an ice-water mixture. 3-(3-Trifluoromethylphenyl)-4-amino-5-isothiazolecarboxamide formed in the above reaction precipitated and the precipitate was collected by filtration and was dried. 3-(3-Trifluoromethylphenyl)-4-amino-5-isothiazole carboxamide, thus prepared and purified, melted at about 124° C. after recrystallization from an ethyl acetate-hexane solvent mixture; yield 0.4 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][CH2:12][CH2:13][CH2:14]Br.[Cl-].[NH4+]>C1COCC1>[Br:11][CH2:12][CH2:13][CH2:14][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: BrCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1ccc(OCCCBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
To a solution of 4-chlorophenol (5.0 g, 38.9 mmol) in dry THF (80 ml) under nitrogen cooled to 0° C. was added portionwise sodium hydride (60% in mineral oil, 171 g, 42.8 mmol). After stirring at 0° C. for 15 mins and room temperature for 30 mins, this mixture was added to a solution of 1,3-dibromopropane (4 ml, 77.8 mmol) in THF (20 ml) under nitrogen cooled to 0° C. The reaction mixture was stirred at room temperature for 30 mins and then heated at reflux for 5 hours. Saturated ammonium chloride solution (50 ml) was added and the mixture concentrated in vacuo. The residue was partitioned between ethyl acetate (150 ml) and water (150 ml). The organic layer was washed with brine (150 ml), dried over magnesium sulphate, filtered and concentrated in vacuo. Purification was by flash chromatography on silica eluting with dichloromethane afforded the title compound as a clear oil (2.6 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:34][C:35]([NH:38][S:39]([C:42]1[S:46][C:45](Br)=[CH:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])[CH3:36].CCCCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]([NH:38][S:39]([C:42]1[S:46][C:45]([C:19]2[N:18]=[CH:17][N:16]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([CH3:15])[N:12]=3)[CH:20]=2)=[CH:44][CH:43]=1)(=[O:40])=[O:41])([CH3:37])([CH3:34])[CH3:36]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(Cl)c3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.4) (0.45 g, 0.76 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.25 g, 0.84 mmol), tetrakis(triphenylphosphine)palladium (0.053 g, 0.046 mmol) in toluene (8 mL) was heated under reflux conditions for 15 h, hexane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.41 g) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@H:18]([CH3:22])[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Clc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
To a mixture of 4-chlorobromobenzene (0.53 g, 2.75 mmol) and 3-(R)-Methyl-piperazine-1-carboxylic acid tert-butyl ester (0.5 g, 2.5 mmol) in toluene (20 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.029 g, 0.032 mmol), BINAP (0.058 g, 0.093 mmol) and sodium-t-butoxide (1.01 g, 10.5 mmol). The resulting mixture was heated 110° C. for 20 h. The solvent was evaporated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. Column chromatography (10% ethyl acetate/hexane) provided the title compound.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C[O:15][B:16](OC)[O:17]C>O1CCCC1.CCOCC>[CH2:7]([C:8]1[CH:13]=[CH:12][C:11]([B:16]([OH:17])[OH:15])=[CH:10][CH:9]=1)[CH2:6][CH3:5]
Reactant: COB(OC)OC
Reactant: BrCCCc1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium shavings (217 mg, 8.9 mmol) in 3 mL of dry tetrahydrofuran under argon, a crystal of iodine along with a solution of 4-bromopropylbenzene (1.69 g, 8.5 mmol) dissolved in 6 mL of tetrahydrofuran was added at such a rate that a gentle reflux was maintained. The solution was refluxed for an additional 0.5 h, cooled to room temperature and added in portions over 10 min to a solution of trimethylborate (924 mg, 8.9 mmol) previously dissolved in 4 mL of dry ether at −78° C. After 30 minutes, the solution was warmed to room temperature; and stirring was continued for 90 min. The reaction was then quenched by the addition of 2 mL of a 10% hydrochloric acid solution. The tetrahydrofuran was removed under reduced pressure and the remaining residue was extracted into diethyl ether (3×25 mL). The combined ether extracts was extracted with 1 M NaOH (3×25 mL) and the resulting aqueous layer was acidified to pH 2.0 using 6N HCl, then reextracted back into diethyl ether (3×25 mL). The combined organic layers was washed with water (1×25 mL), brine (1×25 mL) and dried over magnesium sulfate. Evaporation of solvent left a brown solid which was filtered through a small plug of silica gel using 10% MeOH/CHCl3. Evaporation left 448 mg (32%) of a brown solid, m.p. 90-93° C.
Reaction SMILES: [CH3:1][NH+:2]1[CH2:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH2:4][CH2:3]1.[Cl-]>O>[CH3:1][N:2]1[CH2:3][CH2:4][CH2:5][CH:6]([C:8]([OH:10])=[O:9])[CH2:7]1
Reactant: C[NH+]1CCC=C(C(=O)O)C1
Agent: [Cl-]
Solvent: O
Product: CN1CCCC(C(=O)O)C1
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
Arecaidine hydrochloride (4 grams) (22.6 mmoles) was hydrogenated in water (100 ml) using 10% Pd--C at 40 psi at 25° C. for 24 hours. The catalyst was filtered off and washed with water. The aqueous solution was shaken with BioRad AG1X8 resin (OH- form) (23 ml bed) and after 5 minutes the resin was filtered off and washed with water. The aqueous solution was evaporated to give the title compound (Yield: 2.95 grams, 92%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-])=O.N>C(O)C.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Fe+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1C=O
Temperature: 100 °C

Procedure:
A mixture of 2-nitrobenzaldehyde (10.0 g, 66.2 mmol) and iron(II) sulfate heptahydrate (129 g, 464 mmol) in ethanol (150 mL) and water (150 mL) was heated at 100° C. for 5 min, and then 28% aqueous ammonia (173 mL) was added dropwise carefully at same temperature. The reaction mixture was filtrated through Celite with diethyl ether. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo to give the crude 2-aminobenzaldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:14])=[CH:11][CH:10]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1ccc(Br)cc1
Product: OC(c1ccc(Br)cc1)c1cccnc1

Procedure:
Using the same protocol as described in example 22, step 1, 3-bromopyridine (482 μL, 5.0 mmol) was added to 4-bromobenzaldehyde (1.018 g, 5.5 mmol). The crude residue was chromatographed on silica gel using 1% NH4OH and 9% MeOH in dichloromethane to afford the title compound.
Reaction SMILES: [CH:1]1([CH:4]([OH:18])[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[O:16][CH3:17])[CH2:3][CH2:2]1.C(=O)=O.CC(O)C>CC#N.CC(O)C>[CH:1]1([C@@H:4]([OH:18])[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[O:16][CH3:17])[CH2:3][CH2:2]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(O)C1CC1
Agent: O=C=O
Solvent: CC(C)O
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])ccc1OC[C@H](O)C1CC1

Procedure:
Racemic 1-cyclopropyl-2-(2-methoxy-4-nitrophenoxy)ethanol (45.1 g, mmol) in 2/1 MeCN/i-PrOH (451 mL) was resolved by chiral chromatography resolution using a CHIRALPAK® AD-H (3×25 cm, 5 μm) column under the Chiral-SFC conditions. The chromatographic conditions employed an 85/15 mixture of CO2/i-PrOH as the mobile solvent with a flow rate of 130 mL/min at 35° C. with the BPR pressure maintained at 100 bar and detector wavelength at 234 nM. Each 0.7 mL injection required a run time of 7 min. The chiral purity of the R enantiomer was determined to be greater than 99.9% at 234 nm based on SFC/UV area % using analytical SFC conditions. Concentration of the resultant eluant under vacuum using a rotary evaporator yielded (R)-1-cyclopropyl-2-(2-methoxy-4-nitrophenoxy)ethanol as yellow oil. Subsequent dissolution in 150 ml EtOH and reconcentration yielded the title compound in the form of a yellow oil which solidified to form a light yellow solid (20.9 g) upon drying under high vacuum overnight. M.P. 77° C. 1H NMR (400 MHz, CDCl3): δ 0.30-0.37 (m, 1H), 0.42-0.50 (m, 1H), 0.55-0.69 (m, 2H), 0.97-1.08 (m, 1H), 2.40-2.70 (bs, 1H), 3.41 (ddd, J=8.3, 8.3, 2.7 Hz, 1H), 3.93 (s, 3H), 4.10 (dd, J=9.3, 8.0 Hz, 1H), 4.23 (dd, J=9.3, 2.7 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 7.74 (d, J=2.2 Hz, 1H), 7.89 (dd, J=8.8, 2.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 153.7, 149.2, 141.7, 117.6, 111.5, 106.7, 74.4, 73.5, 56.2, 13.4, 2.7, 2.0. HPLC: 6.26 min retention time, 98.7% API; ZORBAX® column SB C18 4.6×75 mm; flow rate 2.5 ml/min; Gradient solvent system: from 100% A:0% B to 0% A:100% B for 8 min (Solvent A: 10% MeOH 90% H2O=0.2% H3PO4; Solvent B: 90% MeOH−10% H2O+0.2% H3PO4) Detection at 220 run. LC/MS: m/e=254.3 (M+H).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24](N)[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(NC1SC=C(/C(=N/OC(C(OC(C)(C)C)=O)(C)C)/C(O)=O)N=1)=O)(C)(C)C.CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.Cl>ClCCl.O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[CH2:24][C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SC(Sc2c[nH]nn2)C(c2ccccc2)(c2ccccc2)c2ccccc2)CS[C@@H]2CC(=O)N12
Temperature: -30 °C
Reaction time: 0.83 h
Yield: 109.2 %

Procedure:
To a solution of 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester (800 mg : 1.06 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol -4-yl)-2-(1 t-butoxycarbonyl-1methylethoxyimino)acetic acid (479 mg : 1.12 mMol.) in dichloromethane (8 ml) cooling at -30° C., are added N-methylmorpholine (0.27 ml) (2.46 mMol.) and phenyl dichlorophosphate (0.19 ml : 1.27 mMol.), and the mixture is stirred at -30° C. for 50 minutes. The reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (toluene : ethyl acetate=10:1 to 5:1) to give 7β-(Z)-2-(2-t-butoxycarbonylaminothiazol-4 yl)-2-(1-t-butoxycarbonyl -1-methylethoxyimino)acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4carboxylic acid diphenylmethyl ester (855 mg) as yellow foam. Yield : 69%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[CH:5]=[C:6]([CH:9]([F:12])[CH2:10][CH3:11])[C:7]=1[Cl:8].CO.C(#N)C.O>Cl.[Cl-].[Cl-].[Cl-].[Ti+3].C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH:9]([F:12])[CH2:10][CH3:11])[C:7]=1[Cl:8])[NH2:13]
Reactant: CCC(F)c1cc([N+](=O)[O-])cc(Br)c1Cl
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: CC#N
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(F)c1cc(N)cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
6.54 g (22.1 mmol) of 3-bromo-4-chloro-5-(1-fluoropropyl)-1-nitrobenzene was dissolved in a solvent mixture comprising 30 ml of methanol and 90 ml of acetonitrile, followed by the addition of 120 ml of a 20% solution of titanium trichloride in diluted hydrochloric acid under a nitrogen stream under cooling with ice. The obtained mixture was stirred at room temperature for 3 hours and then poured into water. The resulting mixture was extratcted with ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated brine successively, dried and distilled to remove the solvent. The residue was purified by silica gel column chromatography to give 5.04 g of the title compound (yield: 86%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:35])[CH:10]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[Br:36][CH2:37][CH2:38]Br>C(#N)C>[CH3:7][O:8][C:9](=[O:35])[CH:10]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:38][CH2:37][Br:36])=[CH:16][CH:17]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(F)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
To a solution of potassium carbonate (2 kg) in acetonitrile (5000 ml) is added 2-[(2-(4-fluorobenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester (581 g, 1.48 mol) and 1,2-dibromoethane (1000 ml). Then the mixture is stirred at room temperature for 24 hours. After that, the reaction mixture is filtered, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give 2-[(2-(4-fluorobenzoyl)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid methyl ester (429 g, 58%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 4-bromo-2-nitrophenol (5.2 g, 23.8 mmol) in acetone (100 ml) was added potassium carbonate (9.0 g, 65.1 mmol) followed by benzyl bromide (2.6 ml, 21.8 mmol). The resulting mixture was stirred at room temperature for 30 minutes and then heated to reflux overnight. The solids were then removed by filtration, washing with acetone, and the filtrate reduced in vacuo. The residue was dissolved in ethyl acetate and washed with 2M aqueous sodium hydroxide solution (×3) and then brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and reduced in vacuo to afford 4-bromo-2-nitro-1-[phenylmethyl)oxy]benzene (6 g), 92% yield. 1H NMR (500 MHz, CDCl3): δ 5.26 (s, 2H), 7.05 (d, J=8.9 Hz, 1H), 7.42 (m, 5H), 7.63 (dd, J=2.5 Hz, 1H), 8.01 (d, J=2.45 Hz, 1H). 13C NMR (500 MHz, CDCl3): δ 71.6, 112.4, 116.9, 127.1, 128.5, 128.6, 128.9, 135.2, 136.9, 140.7, 151.2.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([NH:22][C:23]([C@@H:25]3[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[CH2:27][N:26]3[CH2:33][C@@H:34]([NH2:36])[CH3:35])=[O:24])[CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1.[CH3:37][C:38]1[C:43]([C:44](O)=[O:45])=[CH:42][N:41]=[CH:40][CH:39]=1.C([O-])(=O)C.[NH4+]>>[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([NH:22][C:23]([C@@H:25]3[CH2:30][O:29][C:28]([CH3:31])([CH3:32])[CH2:27][N:26]3[CH2:33][C@@H:34]([NH:36][C:44]([C:43]3[CH:42]=[N:41][CH:40]=[CH:39][C:38]=3[CH3:37])=[O:45])[CH3:35])=[O:24])[CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1
Reactant: Cc1ccncc1C(=O)O
Reactant: C[C@H](N)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccncc1C(=O)N[C@@H](C)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 79 %

Procedure:
The desired compound was prepared according to Method E from (S)-4-((S)-2-Amino-propyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide trifluoroacetate salt and 4-methyl-nicotinic acid in 79% yield. 1H-NMR (300 MHz, DMSO-d6): δ 1.21 (s,3H), 1.22 (d,3H), 1.36 (s,3H), 2.10 (d,1H), 2.40 (m,1H), 2.62 (m,1H), 2.99 (d,1H), 3.22 (m,1H), 3.94 (m,2H), 4.23 (m,1H), 7.26 (d,1H), 7.90 (s,1H), 8.16 (d,1H), 8.23 (s,1H), 8.34-8.46 (m,3H), 9.02 (s,1H), 10.04 (s,1H), 11.27 (s,1H). Retention Time (LC, method: ammonium acetate standard): 2.22 min.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](O)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][CH:11]=1>FC(F)(F)C(O)=O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:3]2[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([CH3:8])[CH:2]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][CH:11]=1
Reactant: Cc1ccccc1O
Reactant: CCC(O)(CC)c1ccc(Br)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(Br)cc1)c1ccc(O)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
o-Cresol (890 mg, 8.23 mmol) was added to a solution of 3-(4-bromo-phenyl)-pentan-3-ol (Example 143-(1); 2.0 g, 8.23 mmol) in trifluoroacetic acid (20 mL), and the mixture was stirred at room temperature for five hours. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 30:70) to give the target compound as a colorless oil (2.59 g, 94%).