Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([OH:17])[CH:8]=1)=[O:6].[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:5](=[O:6])[NH:4][CH2:3][CH2:2][OH:1])=[CH:8][C:9]1=[O:17])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Reactant: O=C(NCCO)c1cc(O)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCCn1c(=O)cc(C(=O)NCCO)c2ccccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of 4-(2-hydroxy-1-ethylcarbamoyl)-2-hydroxyquinoline (1.2 g), N-(tert-butoxycarbonyl)-6-bromo-hexylamine (2.2 g), cesium carbonate (4 g) and N,N-dimethylformamide (50 ml) was stirred for 6 hours at 60° C. followed by stirring overnight at room temperature. Ice and water were added and the mixture was extracted three times with ethyl acetate. The organic phases were washed with saturated sodium chloride, dried and evaporated to leave a yellow oil which after purification by chromatography on silica gel with ethyl acetate/methanol/aqueous ammonia (45:5:1.5) as eluent gave the desired compound as a light brown solid.
Reaction SMILES: [Na].C([O:4][C:5]([C:7]1[C:8]([S:22][CH2:23][CH2:24]C(OCC)=O)=[N:9][C:10]2[C:15]([C:16]=1[CH3:17])=[CH:14][CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)=[O:6])C.ICC>CO>[CH2:23]([S:22][C:8]1[C:7]([C:5]([OH:6])=[O:4])=[C:16]([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:19])[F:20])=[CH:13][CH:14]=2)[N:9]=1)[CH3:24]
Reactant: CCOC(=O)CCSc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)OCC
Agent: [Na]
Solvent: CO
Solvent: CCI
Product: CCSc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
400 mg (17.4 mmol) sodium were added slowly to MeOH (50 ml) and the solution was stirred for 5 min at RT. Then a solution of 800 mg (2.0 mmol) 2-(3-ethoxy-3-oxopropylthio)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (precursor VVV07) in MeOH (10 ml) was added at RT. The reaction solution was then heated for 30 min at 70° C. After cooling to RT 488 μl (6.0 mmol) 1-iodethane were added and the mixture was stirred for 2 h at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with EE. It was washed with water and the aqueous phase was extracted with EE. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated to small volume under vacuum. 391 mg (1.2 mmol, 62%) 2-(ethylthio)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([C:10]2[C:11]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH:29]=3)=[N:12][C:13]([C:16]([NH:18][C:19]3([C:25]([OH:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])=[CH:14][CH:15]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.S(Cl)(Cl)=O.[CH3:46]O>CCOCC>[ClH:2].[Cl:2][C:3]1[C:4]([C:10]2[C:11]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:40])[CH3:41])[CH:29]=3)=[N:12][C:13]([C:16]([NH:18][C:19]3([C:25]([O:27][CH3:46])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:17])=[CH:14][CH:15]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: CN(C)CCCOc1cc(-c2nc(C(=O)NC3(C(=O)O)CCCCC3)ccc2-c2ncc(Cl)cc2Cl)ccc1Cl
Reactant: CO
Agent: Cl
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(NC(=O)c2ccc(-c3ncc(Cl)cc3Cl)c(-c3ccc(Cl)c(OCCCN(C)C)c3)n2)CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 300 mg (0.47 mmol) of 1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclo-hexanecarboxylic acid hydrochloride in 10 mL of methanol and cooled to 0° C. is added 0.07 mL (0.93 mmol) of thionyl chloride. The reaction mixture is warmed to room temperature and stirred for 20 hours, and then concentrated under reduced pressure. The residue obtained is taken up in 20 mL of ether and solidified. After drying under reduced pressure, 268 mg of methyl 1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylate hydro-chloride are obtained in the form of a white powder.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[C:11]([N:16]3[CH2:20][CH2:19][C@H:18]([F:21])[CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C[Si]([Cl:26])(C)C.N(OC(C)(C)C)=O>C(Cl)Cl>[Cl:26][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[C:11]([N:16]3[CH2:20][CH2:19][C@H:18]([F:21])[CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: N#Cc1nc(-c2ccnc(N)n2)ccc1N1CC[C@H](F)C1
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: N#Cc1nc(-c2ccnc(Cl)n2)ccc1N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 26 %

Procedure:
Compound 78 (970 mg, 3.42 mmol) was dissolved in DCM (50 mL) and trimethyl silyl chloride (1.08 mL, 8.54 mmol) and tert-butyl nitrite (1.02 mL, 8.54 mmol) were added. The reaction mixture was stirred at rt for 60 h. The reaction was quenched with saturated aqueous sodium hydrogen carbonate (50 mL) and extracted with DCM (2×50 mL). The combined organic phases were dried (MgSO4), filtered and solvent removed in vacuo. The crude residue was suspended in toluene (50 mL), diethyl isopropylamine (1.49 mL) and phosphorus oxychloride (5 mL) were added. The resulting mixture was heated under reflux for 3 hours and then poured into ice water with vigorous stirring. The resulting solution was neutralized with sodium hydrogen carbonate and extracted with ethanol (3×100 mL). The combined organic phases were concentrated in vacuo and the residue purified by column chromatography (Biotage SP1, 100% DCM→10% MeOH-DCM) and trituration with EtOAc to afford the title compound (270 mg, 26%) as a pale brown solid. LCMS, Rt=3.03 min (MeOH-FA), m/z 304.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:16][CH2:15][C:10]2([NH:14][CH2:13][CH2:12][CH2:11]2)[C:9]1=[O:17].[CH:18](=O)[CH:19]([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:16][CH2:15][C:10]2([N:14]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12][CH2:11]2)[C:9]1=[O:17]
Reactant: CC(C)C=O
Reactant: O=C1N(c2ccccc2Cl)CCC12CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CN1CCCC12CCN(c1ccccc1Cl)C2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7-(2-Chlorophenyl)-1,7-diazaspiro[4.4]nonan-6-one (20 mg, 0.00008 mol) was dissolved in anhydrous DCM (2 mL). To this mixture was added isobutyraldehyde (8.0 μL, 0.000088 mol) and sodium triacetoxyborohydride (3.0E1 mg, 0.00014 mol). The resulting solution was stirred at RT for 16 h. The volatiles were removed in vacuo and the resulting residue was dissolved in acetonitrile/H2O and purified by prep.-LC/MS chromatography to afford the desired product. LC-MS: 307.1 (M+1H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][CH:13]=2)=[CH:8][C:7]=1[Cl:20])[CH2:2][CH2:3][CH3:4].[NH2:21][C@@H:22]([CH2:26][OH:27])[CH:23]([CH3:25])[CH3:24].C(O)(=O)C.C([BH3-])#N>CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([CH2:18][NH:21][C@H:22]([CH:23]([CH3:25])[CH3:24])[CH2:26][OH:27])[CH:15]=[CH:14][CH:13]=2)=[CH:8][C:7]=1[Cl:20])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)[C@@H](N)CO
Reactant: CCCCOc1ccc(-c2cccc(C=O)n2)cc1Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: CCCCOc1ccc(-c2cccc(CN[C@@H](CO)C(C)C)n2)cc1Cl
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of Example 262A (0.500 g, 1.73 mmol) in MeOH (10 mL) at ambient temperature was added D-valinol (0.20 mL, 1.7 mmol), acetic acid (0.40 ml, 6.9 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.00 g). After 2 hours, the mixture was filtered and concentrated. The residue was partitioned between 1N HCl and ethyl acetate. The organic layer was discarded. The aqueous layer made basic with 1N NaOH and extracted with ethyl acetate. The EtOAc extract was dried (Na2SO4) and concentrated to give 420 mg (65%) of the title compound. MS (DCI+) m/z 377 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J=2.3 Hz, 1H), 7.87 (dd, J=8.6, 2.2 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 7.00 (d, J=4.4 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 4.06-3.92 (m, 2H), 3.69 (dd, J=10.8, 4.0 Hz, 1H), 3.47 (dd, J=10.8, 6.8 Hz, 1H), 2.51 (td, J=6.7, 4.0 Hz, 1H), 1.95-1.78 (m, 4H), 1.63-1.46 (m, 2H), 0.99 (m, 9H).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3]1.[C:19]([OH:22])(=[O:21])[CH3:20]>C([O-])(=O)C.[Ag+].CO>[C:19]([O:22][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3]1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)CCCCCCC1=CC(Br)CC1=O
Reactant: CC(=O)O
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CCOC(=O)CCCCCCC1=CC(OC(C)=O)CC1=O

Procedure:
A mixture of 51.6 g. (0.137 moles) of crude 4-bromo-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one (Example 94), 27 g. (0.162 moles) of silver acetate, and 200 ml. of glacial acetic acid is stirred at reflux for 4.5 hours. The mixture is cooled, and solids are removed by filtration. The filtrate is concentrated and extracted with hot hexane. The extract is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated to give an oil. The crude product is distilled at reduced pressure to give a liquid, b.p. 152°-163°C. (0.01 mm); λ max.MeOH = 223 mμ (10700); ν max. = 1745 (ester carbonyl groups), 1725 (ketone carbonyl groups), and 1235 cm-1 (acetoxy group).
Reaction SMILES: FC(F)(F)C(O)=O.CC([O:12][C:13](=[O:23])[CH2:14][N:15]1[CH2:20][C:19](=[O:21])[NH:18][CH2:17][C:16]1=[O:22])(C)C>C1(OC)C=CC=CC=1>[O:22]=[C:16]1[CH2:17][NH:18][C:19](=[O:21])[CH2:20][N:15]1[CH2:14][C:13]([OH:23])=[O:12]
Reactant: CC(C)(C)OC(=O)CN1CC(=O)NCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)CN1CC(=O)NCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 50 ml round bottom flask 5.0 ml of 70% trifluoroacetic acid acid was added to 2,5-dioxo-1-piperazineacetic acid 1,1-dimethylethyl ester (1.0 g) dissolved in anisole (1 ml). The reaction was stirred at room temperature. The progress of the reaction was monitored by thin layer chromatography. The deprotection rection was sufficiently complete after one hour.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][O:35][CH2:36][CH2:37][OH:38]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:34][O:35][CH2:36][CH2:37][OH:38])=[O:7]
Reactant: NOCCO
Reactant: C=Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: C=Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 78 %

Procedure:
The title compound was prepared from reaction of the product of Example 4, Step A, 3,4-difluoro-2-[(2-fluoro-4-vinylphenyl)amino]benzoic acid with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E, then purified by flash column chromatography on silica gel (10% EtOAc/hexanes) to give 3,4-difluoro-2-[(2-fluoro-4-vinylphenyl)amino]-N-(2-hydroxyethoxy)benzamide as a crystalline white solid (78%); m.p. (EtOAc/hexanes) 134–138° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (br s, 1 H), 8.82 (br s, 1 H), 7.45–7.38 (m, 1 H), 7.37 (dd, J=12.9, 1.8 Hz, 1 H), 7.21–7.15 (m, 1 H), 7.14 (dd, J=8.4, 1.7 Hz, 1 H), 6.83 (td, J=8.7, 4.8 Hz, 1 H), 6.65 (dd, J=17.6, 10.8 Hz, 1 H), 5.73 (d, J=17.9 Hz, 1 H), 5.18 (d, J=11.1 Hz, 1 H), 4.70 (br s, 1 H), 3.85 (t, J=4.8 Hz, 1 H), 3.56 (t, J=4.8 Hz, 2 H). Anal. Calcd for C17H15F3N2O3: C, 58.0; H, 4.3; N, 8.0. Found C, 57.6; H, 4.6; N, 8.1.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][N:22]3[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[CH:36][CH:37]=5)[CH:32]=4)(=[O:30])=[O:29])[C:23]3=[O:43])[CH:19]=2)[CH:14]=[CH:13][N:12]=1.Cl>C(Cl)Cl.O>[O:7]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][N:22]3[CH2:26][CH2:25][CH:24]([NH:27][S:28]([C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[CH:36][CH:37]=5)[CH:32]=4)(=[O:29])=[O:30])[C:23]3=[O:43])[CH:19]=2)[CH:14]=[CH:13][N:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccnc(Cl)c5c4)C3=O)cc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2ccc(S(=O)(=O)NC3CCN(Cc4ccc5ccnc(Oc6ccccc6)c5c4)C3=O)cc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Phenol (6.81 g, 72.4 mmol) and potassium hydroxide ( 0.41 g, 7.31 mmol) are added to 7-methoxynaphthalene-2-sulfonic acid [1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (1.8 g, 3.6 mmol) and heated to 90° C. until a homogeneous mixture is obtained. The mixture is stirred overnight at 90° C., then cooled to room temperature and diluted with methylene chloride (100 mL) and water. The aqueous layer is neutralized to pH 7 using 1 N HCl, then the two layers are separated and the aqueous layer is extracted with additional methylene chloride. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 30% EtOAc/hexanes to 60% EtOAc/hexanes to give the product (1.66 g, 3 mmol) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[O:13](S(C(F)(F)F)(=O)=O)[S:14]([C:17]([F:20])([F:19])[F:18])(=O)=[O:15]>N1C=CC=CC=1>[F:18][C:17]([F:20])([F:19])[S:14]([O:1][C:2]1[C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:12])[C:8]=2[CH:9]=[CH:10][CH:11]=1)(=[O:15])=[O:13]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCCc2c(O)cccc21
Solvent: c1ccncc1
Product: O=C1CCCc2c(OS(=O)(=O)C(F)(F)F)cccc21

Procedure:
A solution of 5-hydroxy-3,4-dihydronaphthalen-1(2H)-one (5 g, 30.8 mmol) in 30 mL of dry pyridine was cooled to −5° C. and Tf2O (10.4 g, 36.96 mmol) was added dropwise. The reaction was warmed to ambient temperaure slowly and stirred over night. Pyridine was distilled off under reduce pressure, and the residue was purified with silica gel cloumn chromatography to give 5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH:29]([CH3:31])[CH3:30])[C@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:15]([CH2:25][C:26](O)=[O:27])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]([CH:29]([CH3:31])[CH3:30])[C@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C@@H:15]([CH2:25][CH2:26][OH:27])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(C(=O)OCc1ccccc1)[C@@H]1CC[C@H](CC(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(C(=O)OCc1ccccc1)[C@@H]1CC[C@H](CCO)N(C(=O)OC(C)(C)C)C1
Yield: 86.5 %

Procedure:
To a solution of [(2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-1-(tert-butoxycarbonyl)-piperidin-2-yl]acetic acid (8.0 g) in tetrahydrofuran (100 mL) was added triethylamine (7.7 mL), and thereto was added ethyl chloroformate (3.5 mL) under ice-cooling. After the mixture was stirred under ice-cooling for one hour, the insoluble materials were removed by filtration. To the filtrate was added dropwise a solution of sodium borohydride (3.5 g) in water (30 mL) under ice-cooling with stirring. Then, the mixture was stirred at room temperature for one hour. To the mixture was added an aqueous potassium hydrogen sulfate solution under ice-cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound (6.7 g) as a colorless oil.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[CH3:11]/[C:12](=[CH:17]\[CH2:18][CH2:19]/[C:20](/[CH3:30])=[CH:21]/[CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)/[CH2:13][CH2:14][CH:15]=[O:16]>O.C(O)(C)(C)C.CC(=CC)C>[CH3:11]/[C:12](=[CH:17]\[CH2:18][CH2:19]/[C:20](/[CH3:30])=[CH:21]/[CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)/[CH2:13][CH2:14][C:15]([OH:6])=[O:16]
Reactant: O=P([O-])(O)O
Reactant: C/C(=C\CC/C(C)=C/COC1CCCCO1)CCC=O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: C/C(=C\COC1CCCCO1)CC/C=C(\C)CCC(=O)O

Procedure:
A.a) A solution of 105 g of 80% sodium chlorite and 100 g of sodium dihydrogen phosphate in 1 l of water is added within 30 min. to 50 g of (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dienal in 1.5 l of tert-butanol and 1.5 l of 2-methyl-2-butene. After 2½ hrs. at room temperature the mixture is concentrated and the residue is taken up in methylene chloride, washed with ice-water and 10% potassium hydrogen sulphate solution and dried. 46.5 g of (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxyl)-deca-4,8-dienoic acid are obtained. The acid obtained is dissolved in 590 ml of methylene chloride and treated at 0° C. with 14.9 ml of N-allyl-methyl-amine, 32.0 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 1.88 g of dimethylaminopyridine. After 3 hrs. at room temperature and working up with methylene chloride/10% potassium hydrogen sulphate and subsequently saturated sodium hydrogen carbonate solution the organic phase is dried and concentrated. 52.3 g of crude (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dienoic acid allyl-methylamide are obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[CH3:14][N:15]1[C:24]2[CH2:23][CH2:22][CH2:21][C:20](=O)[C:19]=2[CH:18]=[CH:17][C:16]1=[O:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH:11][CH:20]2[CH2:21][CH2:22][CH2:23][C:24]3[N:15]([CH3:14])[C:16](=[O:26])[CH:17]=[CH:18][C:19]2=3)=[CH:7][CH:8]=1
Reactant: NCCc1ccc(C(F)(F)F)cc1
Reactant: Cn1c2c(ccc1=O)C(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1c2c(ccc1=O)C(NCCc1ccc(C(F)(F)F)cc1)CCC2
Temperature: 25 °C
Reaction time: 40 h
Yield: 64.1 %

Procedure:
A mixture of 2-(4-trifluoromethylphenyl)ethylamine (4.1 g), 5,6,7,8-tetrahydro-1-methyl-5oxo-2(1H)-quinolinone (3.0 g), and para-toluenesulfonic acid (256 mg) was heated in refluxing toluene (50 ml), with azeotropic removal or water, for 40 hrs. An additional 2.0 g of the amine was added and the mixture was refluxed for 36 hr. The solution was cooled, and the mixture was concentrated in vacuo. Sodium borohydride (0.6 g) was added to a solution of the residue in ethyl alcohol (50 ml), and the resulting mixture was stirred at room temperature for 1 hr. The mixture was concentrated in vacuo, the residue was quenched with water, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate/hexanes to provide, in two crops, 3.8 g (65%) of product, mp 104°-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]#[N:20])([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.O1CCC[CH2:22]1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:11]([CH:10]1[CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([C:19]#[N:20])[CH2:14][CH2:15][C:16]1=[O:18])([O:13][CH3:22])=[O:12]
Reactant: C1CCOC1
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)C1CC(C#N)(c2ccc(Cl)cc2)CCC1=O
Yield: 96 %

Procedure:
A reaction mixture consisting of 34.97 gm. (0.108 mole) dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid, (prepared in Part A, above), dissolved in 700 ml. tetrahydrofuran with 24.4 gm. (0.218 mole) potassium tert-butoxide added is heated at the reflux temperature for 41/2 hours. After cooling, the reaction mixture is chilled in an ice-bath and 175 ml. 2.5 N acetic acid is added. The organic and aqueous phases separate and the organic phase is recovered. It is diluted with 600 ml. benzene before being washed successively with aqueous sodium bicarbonate, water, and brine. The organic solvents are then removed by distillation under reduced pressure. There is thus obtained 30.2 gm. (96% yield) of 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone having a melting point at 139° to 143° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH3:30])[C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O.C(COC)OC>[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH3:30])[C:26]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 5 h

Procedure:
A solution of 2.1395 g of L-proline (18.6 mmol) and 1.56 g of NaHCO3 (18.6 mmol) in water (20 ml) is treated with a solution of 4.138 g of the succinimide ester of N-benzyloxycarbonyl-2(S)-aminobutyric acid (12.4 mmol) prepared as in Example 3 b), in dimethoxyethane (25 ml). After 5 hours, 12.4 ml of water are added, the resulting mixture is acidified to pH=2 with concentrated HCl and is extracted with ethyl acetate. The extracts are dried and are evaporated, which leads to a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[O:7])=[C:4]([O:26][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH:3]=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[O:7])=[C:4]([O:26][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH:3]=1
Reactant: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)NCCN1CCNCC1

Procedure:
The product of step (c) (0.55 g) was dissolved in dichloromethane (15 ml) and trifluoroacetic acid (3 ml) added. After 1 hour the solvent was evaporated and the product obtained as a solid (0.9 g), m.p. 120-122° C.