Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C@H:11]([CH2:21][N:22]3[N:26]=[N:25][C:24]([CH2:27][CH2:28]O)=[N:23]3)[O:10][C:9]2=[O:30])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C@H:11]([CH2:21][N:22]3[N:26]=[N:25][C:24]([CH2:27][CH2:28][N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:23]3)[O:10][C:9]2=[O:30])=[CH:4][CH:3]=1
Reactant: COc1cccc([C@H]2[C@H](Cn3nnc(CCO)n3)OC(=O)N2c2ccc(Cl)cc2)c1
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc([C@H]2[C@H](Cn3nnc(CCN4CCOCC4)n3)OC(=O)N2c2ccc(Cl)cc2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (4S,5S)-3-(4-chlorophenyl)-5-((5-(2-hydroxyethyl)-2H-tetrazol-2-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one (47 mg, 0.11 mmol) in DCM is cooled to 0° C. and treated with methanesulfonyl chloride (10 μL, 0.13 mmol) followed by triethylamine (36 μL, 0.26 mmol). After 30 min., the reaction is quenched with water and extracted with DCM, then dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product is then dissolved in DMF (1 mL) and treated with excess morpholine (48 μL, 0.55 mmol) and heated to 100° C. overnight. The cooled reaction is then quenched with water, basified to pH 10 and extracted with EtOAc. The crude product is purified by preparative HPLC (C-18, 10-90% ACN/water (0.05% TFA)) to give the title compound. 1H NMR (acetone-d6, 400 MHz) δ 7.47-7.43 (m, 2H), 7.34-7.29 (m, 3H), 7.04 (app t, J=2.0 Hz, 1H), 7.00-6.98 (app d, J=7.7 Hz, 1H), 6.90 (ddd, J=8.3, 2.6, 0.9 Hz, 1H), 5.61 (d, J=5.0 Hz, 1H), 5.33 (dd, J=14.6, 5.6 Hz, 1H), 5.25 (dd, J=14.6, 4.1 Hz, 1H), 4.99 (ddd, J=5.6, 5.1, 4.2 Hz, 1H), 3.78 (s, 3H), 3.55 (t, J=4.6 Hz, 4H), 2.99-2.93 (m, 2H), 2.59-2.55 (m, 2H), 2.40-2.37 (m, 4H); HPLC-MS calculated C24H27ClN6O4 (M+H+) 499.2, found 499.2.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (3.50 g) in dimethyl sulfoxide (60 mL) were added L-valine (3.16 g) and cesium carbonate (9.53 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 5.69 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(CC(=O)O)cc1Br
Agent: BrB(Br)Br
Product: O=C(O)Cc1ccc(O)c(Br)c1
Yield: 91.1 %

Procedure:
Proceeding as in Reference 22, but substituting 3-bromo-4-methoxyphenylacetic acid (14.0 g, 0.057 mol) and boron tribromide (63 mL, 1M in dichloromethane, 0.063 mol), gave 3-bromo-4-hydroxyphenylacetic acid (12 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:15]([C:16]#[N:17])=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([O:18][CH2:19][CH3:20])[CH:4]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:21]([CH2:2][C:3]1[C:15]([C:16]#[N:17])=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([O:18][CH2:19][CH3:20])[CH:4]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOc1cc(CBr)c(C#N)cc1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(CN=[N+]=[N-])c(C#N)cc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
After dissolving tert-butyl 4-(bromomethyl)-5-cyano-2-ethoxybenzoate (2.20 g, 70% purity) in dimethylformamide (25 ml), sodium azide (2.1 g) was added and the mixture was stirred at 50° C. for 30 minutes. It was then diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to yield the title compound (1.913 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:29][CH:28]=1
Reactant: Oc1ccc(-c2cccc(F)c2F)cc1
Reactant: OCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: OCCCCCCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Yield: 85 %

Procedure:
First, 3 g of 16-bromo-1-hexadecanol, 1.9 g of 2,3-difluoro-4'-hydroxybiphenyl, 2.6 g of potassium carbonate, and 50 ml of methyl ethyl ketone were placed in a 100 ml flask. The reaction mixture was stirred under reflux for 32 hours. The reaction mixture was poured into water, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was recrystallized from acetone to obtain 3.5 g of 2,3-difluoro-4'-(16-hydroxyhexadecyl)oxybiphenyl (Y: 84%). The compound thus obtained had a purity of 97.4% by GC.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C([O:14][C:15](=O)[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)C.Cl>C1COCC1.C(OCC)(=O)C.O>[Cl:22][C:20]1[CH:21]=[C:16]([CH:17]=[C:18]([Cl:23])[CH:19]=1)[C:15]([CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9])=[O:14]
Reactant: O=C1CCc2sccc21
Reactant: CCOC(=O)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1cc(Cl)cc(Cl)c1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 34 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 ml of THF was treated with NaH (60 percent, 1.5 g, 36 mmol). After the addition of 3,5-Dichloro-benzoic acid ethyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (70 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(3,5-Dichloro-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.5 g, 4.8 mmol) as brown solid in 34% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].O>CN(C=O)C.N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C=CC(=O)Nc1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 94.2 %

Procedure:
A solution of 4-aminobenzoic acid (1.40 g, 10 mmol) in DMF (10 mL) and pyridine (0.5 ml) was cooled to 0° C. To this solution was added of acryloyl chloride (0.94 g, 10 mmol) and the resulting mixture was stirred for 3 hours. The mixture was poured into 200 ml of water and the white solid obtained was filtered, washed with water and ether. Drying under high vacuum provided 1.8 g of the desired product which was used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C=O)C.[NH2:17][C:18]1[N:22]([CH2:23][CH3:24])[N:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Cu+2].C(O)(=O)C.O>[CH2:23]([N:22]1[C:18]([NH:17][C:2]2[C:3](=[CH:7][C:8]([Br:11])=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:19][CH:20]=[N:21]1)[CH3:24]
Reactant: CCn1nccc1N
Reactant: O=C(O)c1cc(Br)ccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCn1nccc1Nc1ccc(Br)cc1C(=O)O
Yield: 45.1 %

Procedure:
A mixture of 2,5-dibromobenzoic acid (25 g, 0.09 mol), DMF (200 ml), 5-amino-1-ethylpyrazole (10 g, 0.09 mol), Cu(OAc)2 (1 g) and K2CO3 (12.3 g, 0.09 mol) was heated at reflux for about 2 days. The reaction mixture was poured into water, acidified with acetic acid and the precipitate which formed was collected by filtration to afford 12.6 g of N-(1-ethylpyrazol-5-yl)-5-bromoanthranilic acid.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=[O:5].CC1C=CC(S(O)(=O)=O)=CC=1.[N:35]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[N:37][CH:36]=1.[BH4-].[Na+]>CS(C)=O>[F:19][C:13]([F:18])([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:20]=[CH:21][CH:22]=[N:23][C:2]=2[NH:1][CH2:41][C:38]2[CH:39]=[CH:40][N:35]=[CH:36][N:37]=2)=[CH:8][CH:9]=1)[C:14]([F:15])([F:16])[F:17]
Reactant: O=Cc1ccncn1
Reactant: Nc1ncccc1C(=O)Nc1ccc(C(F)(F)C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cccnc1NCc1ccncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-N-(4-pentafluoroethyl-phenyl)-nicotinamide (180 mg), TsOH (40 mg) and a solution of pyrimidine-4-carboxaldehyde in DMSO (10 ml) were stirred at 60 C for 6 h. Treated with NaBH4 (200 mg) and stirred for 2 h at RT. MS (ES+): 566.3 (M+H)+; Calc'd for C26H28F5N7O2—565.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:18](=O)[CH2:19][CH3:20])[C:14](=[O:17])[CH2:15][CH3:16])=[CH:4][CH:3]=1.Cl.[NH2:25]O>N1C=CC=CC=1>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:25][O:17][C:14]=2[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCC(=O)C(CCCCCCOc1ccc(Br)cc1)C(=O)CC
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCc1noc(CC)c1CCCCCCOc1ccc(Br)cc1

Procedure:
4-[6-(4-Bromophenoxy)hexyl]-3,5-diethylisoxazole [I; Ar is 4-BrC6H4, Y is O(CH2)6, R is C2H5 ] was prepared from 10.0 g. of 4-[6-(4-bromophenoxy)hexyl]-3,5-heptanedione and 2.0 g. of hydroxylamine hydrochloride in 40 ml. of pyridine according to the procedure of Example 2, part (b), and was obtained in the form of a pale yellow oil, b.p. 190°-195° C. (0.001 mm.); yield 7.3 g.; MIC=12 μg/ml (herpes 2).
Reaction SMILES: Cl.[CH:2]1([NH2:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[N-:13]([C:16]#[N:17])[C:14]#[N:15].[Na+]>O>[C:14]([NH:13][C:16](=[NH:17])[NH:12][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1)#[N:15]
Reactant: N#C[N-]C#N
Reactant: NC1CCCc2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CNC(=N)NC1CCCc2ccccc21
Yield: 18.1 %

Procedure:
A solution of 18.4 grams (g) of 1,2,3,4-tetrahydro-1-naphthylamine hydrochloride and 8.90 g of sodium dicyanamide in 220 milliliters (ml) of water was heated at 95° C. (steam bath) for 21 hours, after which time a viscous oil had precipitated from the hot solution. The reaction mixture was then cooled and extracted with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate and the sodium sulfate removed by filtration. The methylene chloride was then removed by evaporation in vacuo, leaving the crude product as a pale yellow gum. The gum was crystallized from isopropyl acetate to give an off-white, crystalline solid, melting point (mp) 153.5°-156.5° C. Recrystallization from aqueous ethanol gave 3.87 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as a white, crystalline solid, mp 157°-158° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]#[N:12].[Li+].CC([N-]C(C)C)C.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24]>C1COCC1.[Cl-].[NH4+].Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:23](=[O:24])[C:22]([F:29])([F:28])[F:21])[C:11]#[N:12]
Reactant: N#CCCc1cccc(Cl)c1Cl
Reactant: CCOC(=O)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: N#CC(Cc1cccc(Cl)c1Cl)C(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a mixture of 3-(2,3-dichlorophenyl)propanenitrile (100 mg, 0.5 mmol) in THF (20 mL) was added LDA (0.5 mL, 2 N in hexane, 1 mmol) dropwise at −78° C. under nitrogen. The mixture was stirred at −78° C. for 0.5 h. Then ethyl 2,2,2-trifluoroacetate (177.5 mg, 1.25 mmol) was added to the mixture dropwise. This solution was stirred at −78° C. for 5 h and diluted with sat. aq. ammonium chloride solution and 1N hydrochloric acid. This solution was extracted with EA (30 mL*3). The combined organic layers were washed with water and brine, dried over sodium sulphate, concentrated under reduced pressure. The residue was purified by a silica gel chromatography to give the titled product (82 mg, 55%) as a yellow solid; LC/MS: MS (ES+) m/e 296 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 3.03 (dd, J=12.9, 14.1 Hz, 1H), 3.52-3.60 (m, 2H), 7.20-7.32 (m, 2H), 7.43-7.51 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:30]([CH:27]3[CH2:28][CH2:29][O:25][CH2:26]3)=[O:31])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)C1CCOC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCOC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(tetrahydro-furan-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using rac-tetrahydro-3-furoic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a light brown oil. MS m/e: 447.2 [M+H]+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][C:29]([C:40]#[N:41])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.[C:42]([O:47][CH2:48][CH3:49])(=[O:46])[CH:43]([CH3:45])O>O1CCCC1>[C:40]([C:29]1([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:28][CH2:27][CH:26]([C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:16]=[CH:15][C:14]([O:13][CH:43]([CH3:45])[C:42]([O:47][CH2:48][CH3:49])=[O:46])=[CH:19][CH:18]=3)=[CH:21][CH:22]=2)[CH2:31][CH2:30]1)#[N:41]
Reactant: CCOC(=O)C(C)O
Reactant: CCCCCCCCC1(C#N)CCC(c2ccc(-c3ccc(O)cc3)cc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CCCCCCCCC1(C#N)CCC(c2ccc(-c3ccc(OC(C)C(=O)OCC)cc3)cc2)CC1
Reaction time: 1 h

Procedure:
9.6 g of diethyl azodicarboxylate dissolved in tetrahydrofuran is added to a mixture of 19.4 g of 4-(4'-hydroxybiphenyl-4-yl)-1-cyano-1-octylcyclohexane, 6.5 g of ethyl lactate and 13.1 g of triphenylphosphene in 300 ml of tetrahydrofuran, stirring is carried out for one hour at 50°, the mixture is allowed to stand overnight, the solvent is removed and the residue is taken up in 100 ml of hot toluene. After the toluene solution has been cooled to 0°, it is filtered and the product is isolated from the filtrate as usual by chromatography. Optically active ethyl 2-[4'-(4-cyano-4-octylcyclohexyl)biphenyl-4-yloxy]propionate is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][C:14](=[O:16])[CH3:15])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1CC(N)CC2
Reactant: CC(=O)OC(C)=O
Product: COc1cccc2c1CC(NC(C)=O)CC2
Yield: 69 %

Procedure:
Using a procedure similar to that described in Example 1, 0.30 g of 8-methoxy-2-amino-tetralin yielded 0.23 g (69%) of 8-methoxy-2-acetamido-tetralin following treatment with acetic anhydride.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:40])[CH2:19][CH:20]([OH:39])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(O[CH:44](OCC)[CH2:45][CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])C.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:17]([CH:18]1[CH2:19][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[O:39][CH:44]([CH2:45][CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])[O:40]1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8]/[CH:7]=[CH:6]\[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CC(O)CCCCCCC/C=C\C/C=C\CCCCC
Reactant: CCOC(CCCN(C)C)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1CC(CCCCCCC/C=C\C/C=C\CCCCC)OC(CCCN(C)C)O1
Temperature: 80 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A solution of the diol (6Z,9Z,29Z,32Z)-octatriaconta-6,9,29,32-tetraene-18,20-diol (7) (500 mg, 0.89 mmol) and 4,4-Diethoxy-N,N-dimethyl-1-butanamine (301mL, 1.34 mmol) in toluene (10 mL) was treated with PPTS (671 mg, 2.67 mmol) and heated (80° C.). After stirring (1 h) the solution was poured into NaOH (5M aq.) and extracted with CH2Cl2. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was subjected to chromatography (100% EtOAc) to yield 3-(4-((8Z,11Z)-heptadeca-8,11-dien-1-yl)-6-((9Z,12Z)-octadeca-9,12-dien-1-yl)-1,3-dioxan-2-yl)-N,N-dimethylpropan-1-amine (9) (399 mg, 68%) as a colorless oil. Rf 0.5 (10% CH3OH—CH2Cl2);
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C[Mg]Br.N1C=CC=CC=1S[C:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)=[O:17].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1.C(OCC)(=O)C>[CH3:25][O:24][C:22]([C:21]1[CH:26]=[CH:27][C:18]([C:16]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:17])=[CH:19][CH:20]=1)=[O:23]
Reactant: COC(=O)c1ccc(C(=O)Sc2ccccn2)cc1
Reactant: c1cc[nH]c1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)c2ccc[nH]2)cc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of pyrrole (1.68 g) in toluene (40 mL) was added dropwise methyl magnesium bromide in THF (0.93N solution, 27.8 mL) at −20 to −30° C. After the addition, the reaction solution was further stirred for 30 minutes. A solution of methyl 4-[(2-pyridylsulfanyl)-carbonyl]benzoate (8.33 mmol) in toluene (80 mL) was cooled to −78° C., and thereto was added dropwise the above toluene solution via a cannula in such a manner that the temperature of the reaction mixture was not raised over −65° C. After the addition, the reaction solution was stirred at −78° C. for 2 hours, and thereto was added a saturated aqueous ammonium chloride solution (50 mL), and the mixture was warmed to room temperature. To the reaction solution was added ethyl acetate (100 mL), and the organic layer was separated. Further, the aqueous layer was extracted with ethyl acetate (50 mL×2). The organic layers were combined, and washed successively with 9% hydrochloric acid (100 mL), 10% aqueous sodium hydrogen carbonate solution (100 mL), water (100 mL) and a saturated brine (100 mL), dried over magnesium sulfate, filterd and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1→4/1) to give the title compound (1.40 g) as colorless solid.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH2:8]([C:10]1[N:14]([C:15]2[CH:16]=[C:17]([CH:21]3[C:30]([CH3:32])([CH3:31])[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33](O)=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[N:13]=[N:12][N:11]=1)[CH3:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH2:8]([C:10]1[N:14]([C:15]2[CH:16]=[C:17]([CH:21]3[C:30]([CH3:31])([CH3:32])[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[N:13]=[N:12][N:11]=1)[CH3:9]
Reactant: CS(N)(=O)=O
Reactant: CCc1nnnn1-c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nnnn1-c1cccc(C2Nc3ccc(C(=O)NS(C)(=O)=O)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To a suspension of 60% sodium hydride (160 mg, 3.9 mmol) in N,N-dimethylformamide (1.5 mL) was added methanesulfonamide (380 mg, 4.0 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-(5-ethyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.4 mmol) and 1,1′-carbonyldiimidazole (136 mg, 0.84 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{2-[3-(5-ethyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (72 mg, 40%) as a white solid: LC/MS m/e calcd for C22H26N6O3S (M+H)+: 455.55, observed: 455.2.