Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[CH2:19].ClCCl.C(N(CC)CC)C>CN1CCCC1=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]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:19]=[CH:18][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=Cc1cccnc1
Reactant: COC(=O)c1ccc(I)cc1-c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C=Cc2cccnc2)cc1-c1ccccc1
Temperature: 80 °C
Yield: 84.4 %

Procedure:
A mixture of the 4-iodo-2-phenylbenzoic acid methyl ester (6.11 g, 18.1 mmol), prepared as in Example 210C, 3-vinylpyridine (2.85 g, 27.1 mmol), prepared as in Example 210E, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complexed to dichloromethane (1:1) (444 mg, 0.543 mmol) and triethylamine (5.05 g, 36.2 mmol), in 1-methyl-2-pyrrolidinone (30 mL) was degassed with nitrogen and heated at 80° C. for 18 hours. The reaction mixture was diluted with ether, filtered through silica gel, and rinsed with ethyl acetate. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (30% ethyl acetate-hexane) to give the title compound (4.82 g, 84%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1.[CH3:14][O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>CN(C=O)C>[CH3:14][O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:9]1[C:8]2[CH:13]=[C:4]([Cl:3])[CH:5]=[CH:6][C:7]=2[O:11][C:10]1=[O:12]
Reactant: COC(=O)CCCCCCCBr
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)oc2ccc(Cl)cc21

Procedure:
The product is produced as described in example 1 from 3 g. of NaH (80% suspension in mineral oil), 17 g. of 5-chloro-benzoxazolin-2-one (produced in usual manners by subjecting 2-amino-4-chloro-phenol-hydrochloride to reaction with phosgene), 200 cc. of DMF, 23.7 g. of 8-bromo-caprylic acid methyl ester and 3 g. of NaJ.
Reaction SMILES: [Mg].[CH:2]1[CH:7]=[CH:6][C:5]([N:8]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:22](Cl)[CH:23]=[CH2:24]>CCOCC>[C:15]1([N:8]([CH:9]=[CH:14][CH2:13][C:12]2[CH:11]=[CH:10][CH:24]=[CH:23][CH:22]=2)[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: C=CCCl
Agent: [Mg]
Solvent: CCOCC
Product: C(=CN(c1ccccc1)c1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
1.0 g (40 mmol) of magnesium metal was placed in a 300 mL four-neck flask was filled with and the flask under nitrogen atmosphere. 100 mL of ether was added, and stirring was initiated. Then 30 mL of an ether solution of 8.6 g (27 mol) of 4bromotriphenylamine was slowly added by dropwise to the mixture. Adding 3 mL, refluxing was slowly started. In the course of refluxing, the addition of the diethylether solution was continued. Upon completion of the addition, refluxing was carried out for another 20 hour. The Grignard reagent solution was cooled to room temperature and was then combined with 40 mL of an ether solution of 2.1 g (27 mmol) of allyl chloride added slowly. Upon completion of the addition, the mixture was refluxed for 2 hours to complete the reaction. 50 mL of Ice-cold water was then added, and hydrolysis was carried out. The ether layer was extracted, washed once with an aqueous solution of saturated sodium bicarbonate and twice with water. The ether solution was then dried over anhydrous sodium sulfate. The ether was removed, and a white solid over 4-(N,N-diphenylamino)allylbenzene was obtained in an amount of 4.9 g (63.2%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CS(C)=O>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CNCCN1
Reactant: Clc1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Clc1cccnc1N1CCNCC1
Temperature: 80 °C

Procedure:
2,3-Dichloropyridine (15.0 g, 101.6 mmol), piperazine (9.78 g, 113.70 mmol), and triethylamine (14.36 g, 141.95 mmol) were dissolved in 300 mL of DMSO and the resulting mixture was heated at about 80° C. for about 24 h. The reaction mixture was then cooled to room temperature and extracted with a saturated aqueous sodium bicarbonate solution. The organic layer was dried, concentrated, and purified using a silica gel column eluted with a gradient elution from ethyl acetate to 2:1 ethyl acetate:methanol to provide N-(3-chloropyridin-2-yl)-piperazine (compound 1) as a yellow liquid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:14][OH:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C>CS(C)=O.C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([CH:14]=[O:15])[C@@H:10]([CH3:11])[CH2:12][CH3:13])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC[C@H](C)[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
To an ice cold solution of Boc-isoleucinol (3.89 g, 17.9 mmol) in DMSO (15 mL) and DCM (200 mL) was added DIEA (9.7 mL, 55.5 mmol), followed by dropwise addition of a solution of Py.SO3 (8.83 g, 55.5 mmol) in DMSO (50 mL, +10 mL to rinse the funnel). The reaction mixture was stirred at rt for 2 h. After removal of the DCM, the residue was diluted with Et2O (400 mL) and washed with H2O (2×100 mL) and brine (150 mL). The aqueous layer was back extracted with Et2O (100 mL). The combined Et2O layer was washed with saturated NaHCO3 (150 mL) and dried (Na2SO4). The solvent was removed to give the titled compound (3.97 g).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:23][NH:24][C:25](=[O:30])[CH2:26][C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:23][NH:24][C:25](=[O:30])[CH2:26][C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: O=C(O)CC(=O)NCc1cc(F)cc(F)c1
Product: CN1C(=O)C(NC(=O)CC(=O)NCc2cc(F)cc(F)c2)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=450.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-malonamic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.O[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>CO.ClCCl>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH:24]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: Oc1cccnc1
Solvent: ClCCl
Solvent: CO
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Oc1cccnc1
Yield: 14 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-hydroxypyridine (12 mg, 0.13 mmol) as the source alcohol. Chromatography (5% methanol/dichloromethane) through SiO2 yielded 9 mg (14%) of the titled compound. ESI-MS m/z 391 (M+Na+), 367 (M−H−).
Reaction SMILES: [N+:1]([N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:5]([C:13]([OH:15])=O)[CH2:6][CH2:7][CH2:8][NH:9][C:10](=[NH:12])[NH2:11])([O-:3])=[O:2].ClC(OCC(C)C)=O.[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][CH3:36]>O1CCCC1.C(N(CC)CC)C>[N+:1]([N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:5]([C:13]([N:32]([CH2:33][CH2:34][CH2:35][CH3:36])[CH3:31])=[O:15])[CH2:6][CH2:7][CH2:8][NH:9][C:10](=[NH:12])[NH2:11])([O-:3])=[O:2]
Reactant: CCCCNC
Reactant: CC(C)(C)OC(=O)N([C@@H](CCCNC(=N)N)C(=O)O)[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)[C@H](CCCNC(=N)N)N(C(=O)OC(C)(C)C)[N+](=O)[O-]

Procedure:
A 3.2 gram amount of NG -nitro-N2 -(tert-butyloxycarbonyl)-L-arginine was dissolved in a mixture of 40 ml of dry tetrahydrofuran and 1.4 ml of triethylamine. To the solution was added 1.4 ml of isobutyl chloroformate with stirring and cooling in an ice-salt bath. After additional stirring for 15 minutes, 0.87 gram of N-methyl-n-butylamine was added to the mixture. Then the reaction mixture was stirred continuously for 40 minutes at room temperature. The solvent was removed by distillation under reduced pressure, below 40° C. The residue was extracted with 100 ml of ethyl acetate and the extract was washed successively with a 10% aqueous citric acid solution, saturated sodium chloride solution, saturated aqueous sodium bicarbonate solution, and finally with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give NG -nitro-N2 -(tert-butyloxy-carbonyl)-N-(n-butyl)-N-methyl-L-argininamide. This material was added to ethyl acetate containing 10% dry HCl and allowed to stand for 2 hours, and NG -nitro-N-(n-butyl)-N-methyl-L-argininamide hydrochloride was precipitated.
Reaction SMILES: [H-].[Na+].[Cl-].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:5]=1.CN(C)C=O.[Cl:35][C:36]1[CH:65]=[CH:64][C:39]([CH2:40][N:41]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH2:51][C:52]4[CH:61]=[CH:60][C:59]5[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=5)[N:53]=4)=[CH:47][CH:48]=3)[C:43]([CH:62]=O)=[CH:42]2)=[CH:38][CH:37]=1>O.C(OCC)(=O)C>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:40][N:41]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH2:51][C:52]4[CH:61]=[CH:60][C:59]5[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=5)[N:53]=4)=[CH:47][CH:48]=3)[C:43]([CH:62]=[CH:10][C:6]3[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=3)=[CH:42]2)=[CH:64][CH:65]=1
Reactant: O=Cc1cn(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccc(Cn2cc(C=Cc3cccnc3)c3cc(OCc4ccc5ccccc5n4)ccc32)cc1
Reaction time: 0.33 h
Yield: 30.5 %

Procedure:
A suspension of sodium hydride (60%-oil suspension, 0.39 g), 3-picolyl-triphenylphosphonium chloride (2.55 g) and N,N-dimethylformamide was stirred for 20 minutes, followed by the addition of 1-(4-chlorobenzyl)-3-formyl-5-(2-quinolylmethoxy)indole (3.0 g). The mixture was stirred for an additional 10 hours and then poured into water-ethyl acetate (50% v/v). The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resultant crude product was purified by chromatography on silica gel using 50%-ethyl acetate in n-hexanes as eluent to yield 1-(4-chlorobenzyl)-3-(2-(3-pyridyl)ethenyl)-5-(2-quinolylmethoxy)indole (1.0 g), m.p. 169°-171° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14]([CH3:18])(O)[CH:13]([CH2:19][CH3:20])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[O-]S([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[CH2:19]([C:13]1[CH2:12][CH:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][C:14]=1[CH3:18])[CH3:20]
Reactant: CCC1CC(CCOCc2ccccc2)CCC1(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: c1ccccc1
Product: CCC1=C(C)CCC(CCOCc2ccccc2)C1

Procedure:
A mixture of 5-(2-benzyloxy-ethyl)-2-oxo-cyclohexanecarboxylic acid methyl ester in anhydrous MeOH (10 mL) was reacted with NaOMe solution (16.6 mL, 8.28 mmol) at rt for 15 min. Iodoethane (2.76 mL, 34.5 mmol) was added via syringe and the mixture was stored at rt for 48 h. Another portion of NaOMe (8.3 mmol) and EtI (35 mmol) was added and the mixture was allowed to react until the starting material was not present (by TLC). The solution was quenched with an aqueous work-up and the resultant residue was purified by chromatography to yield 5-(2-benzyloxy-ethyl)-1-ethyl-2-oxo-cyclohexanecarboxylic acid methyl ester (Intermediate K2, 1.87 g (86%). The keto-ester (Intermediate K2) was heated at 90° C. in 10% KOH (100 mL) for 10 h, then 6 h at rt. The mixture was cooled to 0° C. and acidified with HCl. The solution was warmed to 40° C. for 15 min. and then stored at rt for 2 h. The mixture was neutralized to pH 7 with NaOH and the organic material was recovered by extraction with chloroform. The resulting 4-(2-benzyloxy-ethyl)-2-ethylcyclohexanone (Intermediate K3) was isolated by standard work-up and used without further purification (88%). Intermediate K3 (1.36 g, 5.24 mmol) was dissolved in THF (75 mL) and treated with MeMgBr (2.62 mL, 7.9 mmol) at 0° C. and reacted at rt for 1 h. The organic material was isolated from an aqueous, acidic work-up and purified by chromatography to give 4-(2-benzyloxy-ethyl)-2-ethyl-1-methylcyclohexanol 1.36 g (94%). 4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol (1.39 g, 5.04 mmol) and TsOH—H2O (0.48 g, 2.52 mmol) were heated to reflux in benzene (˜100 mL) for 18 h in the presence of MgSO4 (˜250 mg). After an aqueous work-up and chromatographic purification, the product [2-(3-ethyl-4-methyl-cyclohex-3-enyl)-ethoxymethyl]-benzene (Intermediate K4) was isolated as a pale yellow oil 0.912 g (71%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCN(CC(F)(F)F)C2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-19 by using (R)-1-((5-chloro-1-(pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and 2,2,2-trifluoroethyl trifluoromethanesulfonate instead of (S)-1-((5-chloro-1-(pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and 2,2,2-trifluoroethyl trifluoromethanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:5]([S:14]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH3:28])([CH3:27])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:4][C:3]=1[C:29]1[C:34]([C:35]#[N:36])=[CH:33][C:32]([C:37]([F:40])([F:39])[F:38])=[N:31][CH:30]=1.C(#N)C.[OH2:44].CO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:29]2[CH:30]=[N:31][C:32]([C:37]([F:39])([F:38])[F:40])=[CH:33][C:34]=2[C:35]#[N:36])=[CH:4][C:5]([S:14]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH3:28])([CH3:27])[CH2:19][CH2:18]2)(=[O:15])=[O:16])=[C:6]([CH:7]=1)[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:44])=[O:13]
Reactant: CC1(C)CCN(S(=O)(=O)c2cc(-c3cnc(C(F)(F)F)cc3C#N)c(Cl)cc2OCCCCO)c2ccccc21
Reactant: O
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: CC1(C)CCN(S(=O)(=O)c2cc(-c3cnc(C(F)(F)F)cc3C#N)c(Cl)cc2OCCCC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5-[2-chloro-5-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(4-hydroxy-butoxy)-phenyl]-2-trifluoromethyl-isonicotinonitrile 11-1 (65 mg, 0.11 mmol) in a mixture of DCM (0.5 mL), acetonitrile (0.5 mL) and water (0.6 mL) was added NalO4 (71 mg, 0.33 mmol) and RuCl3 (4.5 mg, 0.022 mmol). After stirring at rt for 30 minutes, 0.5 mL of methanol was added. The mixture was stirred for 30 minutes, filtered, and purified by prep. LCMS to afford 4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butyric acid 12-1. MS: 608.1 (M+H)+; tR=5.87 min (method 5).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:20][C:21]1[S:25][C:24]([CH:26]=O)=[CH:23][CH:22]=1>[OH-].[K+].CCO>[Cl:20][C:21]1[S:25][C:24]([CH:26]=[C:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:10]=3)[C:15]2=[O:19])=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc(Cl)s2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 77.7 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.25 g, 0.98 mmol) was reacted with 5-chlorothiophene-2-carboxaldehyde (0.215 g, 1.47 mmol) in 5 mL of 4% KOH in EtOH to afford 0.293 g (77%) of the title compound as a coarse cream solid, mp 143-144° C.: APCI-MS m/e 385.5 (M+ +1); 1H-NMR (CDCl3): δ 8.03 (1H, d, J=8.5 Hz), 7.81 (1H, s), 7.65 (1H, s), 7.10 (1H, d, J=3.9 Hz), 7.06 (1H, s), 7.02 (1H, s), 6.91 (1H, d, J=3.9 Hz), 6.80 (1H, dd, J=8.5 Hz, J=2.5 Hz), 6.66 (1H, d, J=2.5 Hz), 4.36 (2H, m), 4.26 (2H, m), 3.05 (2H, m), 2.93 (2H, m).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>>[CH2:1]=[CH:2][C:3](=[CH2:4])[CH3:6].[CH2:6]=[CH:7][C:8]1[CH:2]=[CH:1][CH:11]=[CH:10][CH:9]=1
Reactant: [Li]CCCC
Reactant: CCCCCC
Product: C=CC(=C)C
Product: C=Cc1ccccc1
Temperature: 58 °C
Reaction time: 0.33 h

Procedure:
The resulting mixture is then heated up to a temperature of 45° C. and to it 0.046 g of n-butyl lithium in n-hexane is added. After a 20-minute reaction, the temperature is increased up to 58° C. A sample is collected in order to verify that isoprene has undergone complete conversion, and then 17 g of styrene is added and the reaction is allowed to proceed during a further 20 minutes, until the second monomer has undergone complete conversion too. The temperature of the end mixture results to be of approximately 63° C. In that way, a living diblock isoprene-styrene polymer (I--S) is obtained. In the third reaction step isoprene is added in an amount of 74 g, with the living triblock copolymer of (I1 --S--I2) type being obtained which is submitted to coupling with monobromoethane.
Reaction SMILES: Cl[C:2]([C@H:4]1[C@@H:6](/[CH:7]=[C:8](\[Cl:13])/[C:9]([F:12])([F:11])[F:10])[C:5]1([CH3:15])[CH3:14])=[O:3].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:18]=1[CH2:19][OH:20].N1C=CC=CC=1.C1(C)C=CC=CC=1>C(OCC)C>[Cl:13]/[C:8](/[C:9]([F:12])([F:11])[F:10])=[CH:7]\[C@@H:6]1[C@H:4]([C:2]([O:20][CH2:19][C:18]2[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:17]=2[Cl:16])=[O:3])[C:5]1([CH3:15])[CH3:14]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: OCc1c(F)cccc1Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)OCc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.4 %

Procedure:
A mixture of (±)-cis-1-chlorocarbonyl-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane (0.82 g), 2-chloro-6-fluorobenzyl alcohol (1.0 g), pyridine (0.275 g) and dry toluene (50 ml) was stirred at the ambient temperature (ca. 25° C.) for a period of 6 hours and then kept for a further period of 72 hours without stirring. The mixture was diluted with diethyl ether (350 ml) and the resultant mixture washed with water, with dilute aqueous sodium carbonate solution, and then dried over anhydrous magnesium sulphate. The solvents were evaporated and the residual oil purified by preparative thick layer chromatography using silica gel plates and diethyl ether as eluent. The oil which was obtained was then distilled to yield 2-chloro-6-fluorobenzyl(±)-cis-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylate (0.67 g) b.p. 150°/0.05 mm Hg.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]1[C:26](=[O:27])[N:6]2[C:7]([C:23]([OH:25])=[O:24])=[C:8]([CH2:11][S:12][C:13]3[N:17]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[N:16]=[N:15][N:14]=3)[CH2:9][S:10][C@H:5]12.C([O-])(=O)C.[K+].[CH3:33][CH:34]([CH2:42][CH3:43])[CH2:35][C:36]([O:38][CH:39](I)[CH3:40])=[O:37].[Cl:44]CCl>CN(C)C=O>[ClH:44].[ClH:1].[NH2:3][C@@H:4]1[C:26](=[O:27])[N:6]2[C:7]([C:23]([O:25][CH:39]([O:38][C:36](=[O:37])[CH2:35][CH:34]([CH3:33])[CH2:42][CH3:43])[CH3:40])=[O:24])=[C:8]([CH2:11][S:12][C:13]3[N:17]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[N:16]=[N:15][N:14]=3)[CH2:9][S:10][C@H:5]12
Reactant: ClCCl
Reactant: CCC(C)CC(=O)OC(C)I
Reactant: CN(C)CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)CC(=O)OC(C)OC(=O)C1=C(CSc2nnnn2CCN(C)C)CS[C@@H]2[C@H](N)C(=O)N12
Temperature: 0 °C

Procedure:
To a solution of 4.22 g of 7β-amino-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylic acid.dihydrochloride in 60 ml of dimethylformamide, 1.67 g of potassium acetate was added and the mixture was cooled to 0° C. with stirring. To the mixture, 5.0 g of 1-iodoethyl 3-methylvalerate was added dropwise, and the mixture was stirred at 0° C. for 5 minutes. The reaction mixture was then poured into a mixture of 60 ml of dichloromethane and 60 ml of 0.1 NHCl, and the aqueous layer was separated. The aqueous layer was adjusted to pH 6.0 with a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was admixed with water and adjusted to pH 2.0 with 4N HCl. The aqueous layer was separated and dichloromethane was removed from the aqueous layer under reduced pressure. The aqueous layer was lyophilized to give 2.83 g of the titled compound.
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[CH:9]12[CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][C:10]2=[O:16].C(Br)C=C.Cl>O1CCCC1.CCCCCC.O1CCCC1>[CH2:3]([CH:11]1[CH:12]2[CH2:15][CH:9]([CH2:14][CH2:13]2)[C:10]1=[O:16])[CH:1]=[CH2:2]
Reactant: O=C1CC2CCC1C2
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: CCCCCC
Product: C=CCC1C(=O)C2CCC1C2
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To 194 ml (388 mmol) of a 2M solution of lithium diisopropyl amide in tetrahydrofuran-hexane, 50 ml of a solution of 38.9 g (353 mmol) of (+)-2-norbornanone in tetrahydrofuran was added dropwise at -40° C., and the mixture was stirred at -20° C. for 30 minutes. Then, 30 ml of a solution of 47.0 g (388 mmol) of allyl bromide in tetrahydrofuran was added dropwise, the mixture was stirred at -20° C. for 30 minutes, the temperature of the mixture was raised to room temperature, and the mixture was stirred for one hour. On ice cooling, the reaction mixture was poured into 300 ml of 2N hydrochloric acid, and the mixture was extracted with toluene (200 ml×4). The extract was washed with successive, saturated sodium bicarbonate solution, water, saturated sodium chloride (each 200 ml), and dried over anhydrous magnesium sulfate. The solution was filtered, and the solvent was distilled off to obtain 77.6 g of crude 3-allyl-2-norbornanone. The crude product was purified by distillation, and 42.5 g (134 mmol) of (+)-exo-3-allyl-2-norbornanone was obtained. Yield: 80%.