Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24](OCC)=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][NH:35][C:34]1=[O:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][NH:35][C:34]4=[O:38])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCCN1CCNC1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Product: O=C(NCCN1CCNC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 31 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.15 mmol) and 1-(2-aminoethyl)-2-imidazolidinone (0.4 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-N-[2-(2-oxo-1-imidazolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide (22 mg, 31% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.25 (br s, 1 H), 8.55 (s, 1 H), 7.46 (s, 1 H), 7.16-7.12 (m, 2 H), 7.03-7.12 (m, 2 H), 4.73 (br s, 1 H), 4.29 (br s, 2 H), 4.11 (s, 2 H), 3.64-3.39 (m, 10 H), 1.79 (m, 2 H); HRMS m/z calcd for C24H27N5O5F: 484.1996. Found: 484.1997.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][NH:4][C:3]1=[O:8].[H-].[Na+].[Br:11][CH2:12]CBr.[CH3:15]N(C)C=O>>[Br:11][CH2:12][CH2:1][N:2]1[C:6](=[O:7])[CH2:5][N:4]([CH3:15])[C:3]1=[O:8]
Reactant: BrCCBr
Reactant: CN1C(=O)CNC1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CN1CC(=O)N(CCBr)C1=O
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a stirred solution of 25 parts of 3-methyl-2,4-imidazolidinedione in 198 parts of N,N-dimethylformamide were added portionwise 1.6 parts of a sodium hydride dispersion 50% under nitrogen atmosphere (exothermic reaction, cooling). Upon complete addition, stirring was continued for 1 hour at room temperature. 45.5 parts of 1,2-dibromoethane were added dropwise. Upon completion, the whole was stirred for 2 days at room temperature. The reaction mixture was evaporated and the residue was taken up in a mixture of water and dichloromethane. The separated organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 35.8 parts (73.6%) of 3-(2-bromoethyl)-1-methyl-2,4-imidazolidinedione as a residue (int. 33).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:24][NH:23][CH2:22][CH2:21][N:20]3[C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:35](=O)[CH3:36].ClC1C=C(NC(N2CCN(C[C@@H]3OCCN(CCC4C=NC=CC=4)C3)CC2)=O)C=CC=1Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH:19]3[CH2:24][N:23]([CH2:35][CH3:36])[CH2:22][CH2:21][N:20]3[C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(CC2CNCCN2C(=O)OCc2ccccc2)CC1
Reactant: CC=O
Agent: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@H]2CN(CCc3cccnc3)CCO2)CC1
Product: CCN1CCN(C(=O)OCc2ccccc2)C(CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Yield: 18 %

Procedure:
Benzyl 2-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)methyl]piperazine-1-carboxylate and acetaldehyde were used in a similar manner to N-(3,4-dichlorophenyl)-4-{[(25)-4-(2-pyridin-3-ylethyl)morpholin-2-yl]methyl}piperazine-1-carboxamide, except that after purification of the residue on a Redisep® silica column, eluting with ethyl acetate/MeOH (30:70), the solid, after precipitation from CH2Cl2 with isohexane, was further purified on an SCX column, eluting sequentially with ethyl acetate, MeOH and 1% ammonia/MeOH to give the title product (20 mg, 18%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH2:24][O:25][C:26]2[C:31]([F:32])=[CH:30][C:29](Br)=[CH:28][C:27]=2[F:34])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C>[F:32][C:31]1[CH:30]=[C:29]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)[CH:28]=[C:27]([F:34])[C:26]=1[O:25][CH2:24][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Reactant: Fc1cc(Br)cc(F)c1OCc1ccccc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cc(-n2ccc3c(OCc4ccccc4)cccc32)cc(F)c1OCc1ccccc1
Temperature: 140 °C

Procedure:
4-[(phenylmethyl)oxy]-1H-indole (500 mg, 2.24 mmoL), 4-bromo-2,6-difluorophenyl phenylmethyl ether (prepared as described in part a), 559 mg, 1.87 mmoL), K3PO4 (990 mg, 4.67 mmoL) and L-Proline (43 mg, 0.373 mmoL) were dissolved in DMF (5 mL) in a microwave vial and degassed by sonication under a flow of argon. To this was added CuI (71 mg, 0.373 mmoL) and the solution was heated to 140° C. in the microwave reactor. After 3 hours the mixture was partitioned between ethyl acetate (100 mL)/water (100 mL), the phases were separated and the aqueous phase re-extracted with ethyl acetate (100 mL). The combined organic phases were washed with sat. NH4Cl (2×100 mL), water (100 mL) and brine (2×100 mL) and finally dried over MgSO4. The crude product was purified by flash chromatography (Biotage SP4, 40+S Cartridge) eluting with a gradient of 0 to 20% Et2O in hexane to give the title compound (D21), (299 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][Cl:16].[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[Cl-:16].[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][P+:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(OC)c2ccccc12
Product: [Cl-]
Yield: 73.8 %

Procedure:
A solution of 4.73 g of 1,4-dimethoxy-2-naphthylmethyl chloride (prepared as described in Preparation 29) and 6.29 g of triphenylphosphine in 50 ml of dry acetonitrile was heated under reflux for 2 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the resulting crystalline residue was washed with diethyl ether and air-dried, to give 7.36 g of the title compound as a white powder, melting at 244°-246° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][CH:15]=[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:11]3=[N:10][C:9]=2/[CH:23]=[CH:24]/[C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)=[CH:4][CH:3]=1.[N:35]1[N:36]=[C:37]([SH:40])[NH:38][CH:39]=1.CC(C)([O-])C.[K+].O>CC(N(C)C)=O>[N:35]1[N:36]=[C:37]([S:40][C:2]2[N:7]=[CH:6][C:5]([C:8]3[N:12]4[N:13]=[CH:14][CH:15]=[C:16]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[C:11]4=[N:10][C:9]=3/[CH:23]=[CH:24]/[C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:4][CH:3]=2)[NH:38][CH:39]=1
Reactant: Clc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Reactant: Sc1nnc[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C(=C/c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(Sc2nnc[nH]2)nc1)\c1ccc2ccccc2n1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A solution of compound 49a (0.50 g, 1.1 mmol) in DMA (3 mL) was treated with 4H-1,2,4-triazole-3-thiol (0.16 g, 1.6 mmol) and potassium tert-butoxide (0.24 g, 2.1 mmol). The resulting mixture was stirred at 140° C. for 3 h, allowed to cool to rt and treated with water (10 mL). The solids obtained were collected by filtration and purified by RP Prep-HPLC. The title compound 22 was obtained as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 14.65 (s, 1H), 8.86 (s, 1H), 8.74 (s, 1H), 8.31 (d, J=8.7 Hz, 1H), 8.13 (d, J=5.7 Hz, 1H), 8.08-8.05 (m, 1H), 7.99-7.92 (m, 3H), 7.81-7.70 (m, 3H), 7.58-7.52 (m, 1H), 7.36 (d, J=7.8 Hz, 1H), 6.44 (d, J=6.0 Hz, 1H), 4.15-4.05 (m, 4H), 3.85-3.75 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H23N9OS: 534.2 (M+H). Found: 534.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)[CH:6]=[CH:7][CH:8]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(CN)c3)cc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(CNS(C)(=O)=O)c3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A solution of N-{5-[3-(aminomethyl)phenyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide (69 mg, 0.2 mmol) in dichloromethane (5 ml) was treated with triethylamine (40 mg, 0.4 mmol), followed by methanesulfonyl chloride (25 mg, 0.22 mmol) and the wole mix stirred at room temperature under argon for 1 h. The reaction mix was washed with 0.5M hydrochloric acid, and the organic layer was evaporated under reduced pressure to give a brown oil which was purified by column chromatography on a 1 g SCX column eluting from 0-50% ethyl acetate in 40-60° C. petroleum ether to give the title compound as a yellow oil (46 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][SH:18].C(=O)([O-])[O-].[Cs+].[Cs+].I[C@H:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]1>CN(C)C=O>[C:34]([O:33][C:32]([NH:31][C@H:28]1[CH2:29][CH2:30][C@@H:26]([S:18][CH2:17][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=3)[O:6][C:2]=2[CH3:1])[CH2:27]1)=[O:38])([CH3:37])([CH3:35])[CH3:36]
Reactant: COC(=O)c1ccc(-c2nc(CS)c(C)o2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](I)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS[C@@H]3CC[C@H](NC(=O)OC(C)(C)C)C3)c(C)o2)cc1
Temperature: 35 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a solution of methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate (870 mg, 3.30 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) maintained under an atmosphere of nitrogen at 35° C. was added cesium carbonate (2.5 g, 7.65 mmol, 2.32 equiv). After stirring at 35° C. for 20 min, tert-butyl N-[(1S,3S)-3-iodocyclopentyl]carbamate (1.25 g, 4.02 mmol, 1.22 equiv) was then added. The resulting solution was allowed to stir for 50 min at 35° C. under nitrogen after which the product was precipitated by the addition of 50 mL water. The solid was collected by filtration, washed with water then dried in a vacuum oven to give 1.35 g (91%) of methyl 4-[4-([[(1R,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentyl]sulfanyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[O:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].[CH3:17][N:18]=[C:19]=[O:20]>C(N(CC)CC)C.ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[O:14][C:13](=[O:15])[N:12]([C:19](=[O:20])[NH:18][CH3:17])[C:11]1=[O:16]
Reactant: COc1cccc(Cl)c1C1OC(=O)NC1=O
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CNC(=O)N1C(=O)OC(c2c(Cl)cccc2OC)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(2-Chloro-6-methoxyphenyl)oxazolidin-2,4-dione (1.21 g., 5 mmoles) was suspended in 25 ml. of 1,2-dichloroethane. Triethylamine (1 drop) and then methyl isocyanate (285 mg., 0.29 ml., 5 mmoles) were added and the mixture stirred for 3 hours at room temperature, by which time solution had resulted. The reaction mixture was diluted with 50 ml. of 1,2-dichloroethane, washed with two portions of saturated sodium bicarbonate and then with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to product. Recrystallization from chloroform-hexane afforded purified 5-(2-chloro-6-methoxyphenyl)-3-methylcarbamoyloxazolidin-2,4-dione [1.04 g., 70%; m.p. 124°-127° C. (dec); m/e 300/298].
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([CH2:21]O)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[NH:28]1[CH2:33][CH2:32]O[CH2:30][CH2:29]1.C(S(C1C=C(C2C=C(CN(C)C)C=C3C=2C2C=C(C)C=N[C:48]=2[NH:49]3)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([CH2:21][N:28]3[CH2:33][CH2:32][N:49]([CH3:48])[CH2:30][CH2:29]3)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(CO)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2cc(CN(C)C)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: C1COCCN1
Product: CCS(=O)(=O)c1cccc(-c2cc(CN3CCN(C)CC3)cc3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 133 and morpholine according to the procedure outline for the preparation of Compound 134. 1H NMR (400 MHz, CD3OD) δ 8.39 (br s, 1H), 8.23 (s, 1H), 8.12 (d, 1H, J=7.6 Hz), 8.05 (s, 1H), 8.03 (d, 1H, J=7.6 Hz), 7.90 (t, 1H, J=7.6 Hz), 7.83 (s, 1H), 7.49 (s, 1H), 4.38 (s, 2H), 3.48-3.56 (m, 2H), 3.26-3.40 (m, 6H), 2.95 (s, 3H), 2.41 (s, 3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C26H30N4O2S, 463; found 463.
Reaction SMILES: C(N(CC)CC)C.[CH:8](=[N:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30].C(OCC)C>ClCCl>[CH:8](=[N:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([S:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)(=[O:31])=[O:30])[CH2:21][CH2:22]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C(=NCC1CCNCC1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: O=S(=O)(c1ccccn1)N1CCC(CN=Cc2ccccc2)CC1
Reaction time: 14 h
Yield: 68.4 %

Procedure:
Triethylamine (6.3 ml) was added to a cloudy solution of N-benzylidene-4-piperidylmethylamine (4.05 g) and pyridine-2-sulphonyl chloride (4.0 g) in dichloromethane (100 ml) and the resulting clear yellow solution was stirred for 14 hours. Removal of the solvent under reduced pressure gave a yellow solid which on addition of diethyl ether (100 ml) partly dissolved. The insoluble white solid (triethylamine hydrochloride) was removed by filtration. Evaporation of the filtrate afforded a flocculent yellow solid which recrystallised from ethanol to give 4-[N-(benzylidene)aminomethyl]-1-(2-pyridinesulphonyl)piperidine as a white crystalline solid (4.7 g).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11]1)=[O:7])(C)(C)C.[C:20](Cl)(=[O:22])[CH3:21].[NH2:24][C:25]1[C:33]([Cl:34])=[CH:32][C:28](C(O)=O)=[C:27]([O:35][CH3:36])[CH:26]=1>>[C:20]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:10]([CH2:9][NH:8][C:6](=[O:7])[C:28]2[CH:32]=[C:33]([Cl:34])[C:25]([NH2:24])=[CH:26][C:27]=2[O:35][CH3:36])[CH2:11]1)(=[O:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(=O)Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNC(C)=O)C1

Procedure:
4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butylamine (1.05 g) as starting compound was reacted and treated in the same manner as in Example 1 using acetyl chloride (0.30 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.78 g) to give N-(1-(4-acetylaminobutyl)pyrrolidin-3-ylmethyl)-4-amino-5-chloro-2-methoxybenzamide.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]3[O:18][CH2:19][O:20][C:12]3=[CH:11][C:10]=2[CH:9]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:33]=2[Cl:34])=[CH:24][CH:23]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[ClH:34].[ClH:34].[Cl:34][C:33]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH:9]2[C:10]3[CH:11]=[C:12]4[O:20][CH2:19][O:18][C:13]4=[CH:14][C:15]=3[CH2:16][CH2:17][NH:8]2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2C1Cc1ccc(-c2cnccc2Cl)cc1)OCO3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: Clc1ccncc1-c1ccc(CC2NCCc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[4-(4-chloropyridin-3-yl)benzyl]-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinoline-6-carboxylic acid tert-butyl ester 40 (0.220 g, 0.459 mmol) in anhydrous dichloromethane (10 mL) was added trifluoroacetic acid (4.190 g, 36.744 mmol) at 0° C., the reaction mixture was warmed to room temperature and stirred at the same temperature for 2 h. The mixture was concentrated under reduced pressure, repeatedly evaporated using dichloromethane. The residue was treated with aqueous HCl and filtered. The filtrates were basified using 1N NaOH, extracted with CHCl3, washed with water, dried over Na2SO4 and evaporated under reduced pressure. The oily mass was dissolved in MeOH (15 mL) and then in diethyl ether (60 mL). 2 M HCl solution in diethylether (30 mL) was added to above solution at 0° C., the mixture was warmed to room temperature and stirred overnight. Filtered the reaction mixture, the residue was washed with ether, crystallized from methanol-ether to afford 42 as off white-solid (0.103 g, 50%). 1H NMR (300 MHz, DMSO-d6) δ 9.33 (bs, 2H, —NH2), 8.62 (s, 1H, ArH), 8.59 (d, J=5.4 Hz, 1H, ArH), 7.76 (d, J=5.4 Hz, 1H, ArH), 7.55 (s, 4H, ArH), 6.83 (s, 1H, ArH), 6.79 (s, 1H, ArH), 6.00 (s, 2H, —CH2), 4.72 (s, 1H, —CH—), 3.48-3.17 (m, 4H, 2*—CH2), 3.08-2.86 (m, 2H, —CH2). MS (ES+) m/z 379 [M-(2HCl)+H]+.
Reaction SMILES: C[O:2][CH:3]=[CH:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.O>O1CCCC1>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1)#[N:17]
Reactant: COC=CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc([C@H]2CC[C@H](CCC=O)CC2)cc1

Procedure:
A solution of 2.04 g of p-[trans-4-(3-methoxy-2-propenyl)cyclohexyl]benzonitrile in 100 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was heated to reflux for 1 hour. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated, whereby 1.9 g (99%) of 3-[trans-4-(p-cyanophenyl)cyclohexyl]propionaldehyde were obtained as colourless crystals; Rf-value (ethyl acetate/petroleum ether vol. 10:90) 0.15.
Reaction SMILES: [N+:1](=[CH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N-].B(F)(F)F.CCOCC.[Cl:22][CH2:23][C:24]#N>ClCCl>[Cl:22][CH2:23][C:24]1[O:12][C:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:3][N:1]=1
Reactant: [N-]=[N+]=CC(=O)Cc1ccccc1
Reactant: N#CCCl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: ClCc1ncc(Cc2ccccc2)o1
Yield: 61.6 %

Procedure:
1-Diazo-3-phenyl-2-propanone (0.8 g, 5 mmol) in dichloromethane (5 ml) was added to a mixture of boron triflouride diethyl etherate (1.2 ml, 10 mmol), chloroacetonitrile (6.4 ml, 100 mmol) and dichloromethane (5 ml) at 20° C. After 0.5 h at 20° C. the solution was washed with cold aqueous 20% sodium hydroxide, dried (MgSO4), and evaporated under reduced pressure to give an oil which was purified by chromatography (10 g silica, dichloromethane) to give 2-chloromethyl-5-benzyl oxazole as a yellow oil (0.64 g, 62%); δH (CDCl3) 7.2(5H, S, aryl), 6.7(1H, S, het-H), 4.5(2H, S, CH2Cl), 4.2(2H, S, CH2Ar), 2-Chloromethyl-5-benzyloxazole (0.6 g, 3 mmol) and triethyl phosphite (0.7 ml, 4.5 mmol) were heated together for 1 h at 160° C. and then cooled. Direct chromatography (10 g silica, 0 to 5% methanol in dichloromethane) then gave diethyl 5-benzyl-2-oxazolylmethyl phosphonate as a light brown oil (0.65 g, 70%); δH (CDCl3) 7.2(5H, S, aryl), 6.7(1H, S, het-H), 4.1(4H, m, OCH2), 3.9(2H, S, CH2Ar), 3.3(2H, d, CH2P), 1.3(6H, t, Me).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[C:6]([S:25][CH2:26][CH2:27][CH2:28][OH:29])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[C:6]([S:25][CH2:26][CH2:27][CH2:28][O:29][S:1]([CH3:4])(=[O:3])=[O:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
Mesyl chloride (6 μl, 0.075 mmol) was added to a solution of 3-tritylsulfanyl-propan-1-ol (5 mg, 0.015 mmol) and triethyl amine,(32 μl, 0.23 mmol) in THF (1 ml). After 30 minutes THF was evaporated under reduced pressure and the crude product dissolved in DCM, washed with a saturated solution of sodium hydrogencarbonate in water, a saturated solution of sodium chloride and dried with MgSO4. A yield of 10 mg was obtained after evaporation under reduced pressure (analytical HPLC: column Luna C18, 00B-4251-E0: solvents: A=water/0.1% TFA and B=CH3CN/0.1% TFA; gradient 40-80% B over 10 min; flow 1.0 ml/minute; retention time 7.12 minutes detected at 214 and 254 nm). Structure verified by NMR.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O1CCCC1.C1(N=C=NC2CCCCC2)CCCCC1.[C:30]([NH:51][CH2:52][CH2:53]O)(=[O:50])[CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH2:36][CH:37]=[CH:38][CH2:39][CH:40]=[CH:41][CH2:42][CH:43]=[CH:44][CH2:45][CH:46]=[CH:47][CH2:48][CH3:49]>CN(C)C1C=CN=CC=1.ClCCCl>[C:1]([O:9][CH2:53][CH2:52][NH:51][C:30](=[O:50])[CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH2:36][CH:37]=[CH:38][CH2:39][CH:40]=[CH:41][CH2:42][CH:43]=[CH:44][CH2:45][CH:46]=[CH:47][CH2:48][CH3:49])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)NCCO
Reactant: O=C(O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)NCCOC(=O)c1cccnc1
Yield: 96.5 %

Procedure:
To a solution of 77 mg (0.63 mmol) of nicotinic acid in a mixed solvent of tetrahydrofuran (2 ml) and 1,2-dichloroethane (2 ml) at room temperature were successively added in an atmosphere of argon 7 mg (0.06 mmol) of 4-dimethylaminopyridine, 129 mg (0.63 mmol) of N,N'-dicyclohexylcarbodiimide and 196 mg (0.57 mmol) of N-5,8,11,14,17-eicosapentaenoyl-2-aminoethanol, which were dissolved in 1,2-dichloroethane (1.5 ml), respectively. The mixture was reacted overnight, and precipitates then produced were separated by filtration and washed with benzene. To the mother liquor was added water, and the mixture was extracted three times with dichloromethane. The organic layer from the extraction was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure to give 311 mg of extraction residue, which was subjected to silica gel column chromatography. From a fraction eluted with chloroform-methanol (98:2) was obtained 246 mg (0.55 mmol) of N-(5,8,11,14,17-eicosapentaenoyl)-2-aminoethyl nicotinate. Physicochemical properties of the product supports the formula (III) shown below.