Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C@H:6]1[C@@H:11]([N:12]([C:21](=[O:35])[CH2:22][C:23]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25](=[O:34])(=[O:33])[N:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]2[CH2:36][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])C.[O-]CC.[Na+].Cl>C(O)C>[O:34]=[S:25]1(=[O:33])[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:23]([C:22]2[C:21](=[O:35])[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C@@H:11]3[C@H:6]([C:4]=2[OH:5])[C@@H:7]2[CH2:36][C@H:10]3[CH2:9][CH2:8]2)[NH:24]1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2ccccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1C(C2=Nc3ccccc3S(=O)(=O)N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
The crude (1S,2R,3S,4R)-3-[[2-(1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(4-fluoro-benzyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester was dissolved in ethanol (8 mL), and a 21 wt. % solution of sodium ethoxide in ethanol (1.6 mL, 4.2 mmol) was added into the above solution. The mixture was stirred at 60° C. for 4 h and allowed to cool down to 25° C. The mixture was poured into 0.5M aqueous hydrochloric acid solution (100 mL). The product started to precipitate and was collected by vacuum filtration. The precipitate was purified by flash column chromatography (Teledyne Isco RediSep column; 100% ethyl acetate) to afford the desired product, (1R,2S,7R,8S)-5-(1,1-dioxo-1,2-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.242 g, 0.517 mmol, 62.1% over two steps), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.16-1.22 (2H, m), 1.40-1.60 (4H, m), 2.51 (1H, bs), 2.64 (1H, d, J=2.1 Hz), 3.03 (1H, d, J=8.0 Hz), 3.54 (1H, d, J=9.3 Hz), 4.42 (1H, d, J=15.6 Hz), 4.97 (1H, d, J=15.7 Hz), 7.15 (2H, t, J=8.8 Hz), 7.33 (2H, dd, J1=8.0 Hz, J2=5.9 Hz), 7.45-7.53 (2H, m), 7.67-7.71 (1H, m), 7.85 (1H, d, J=7.9 Hz). LC-MS (ESI) calcd for C24H22FN3O4S 467.13, found 468.2 [M+H+]. Anal. calcd for C24H22FN3O4S: C, 61.66; H, 4.74; N, 8.99; found C, 61.96; H, 4.88; N, 8.99.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[CH:5]=[CH:6][CH:7]=1.C(N(S(F)(F)[F:20])CC)C.O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][F:20])[CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCCCCc1cccc(Br)c1
Solvent: ClCCl
Solvent: O
Product: FCCCCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 5-(3-bromophenyl)pentan-1-ol (0.63 g, 2.6 mmol) in methylene chloride at −78° C. was treated with a solution of diethylamino sulfur trifluoride (DAST) (0.7 mL, 5.2 mmol) in methylene chloride, allowed to warm to room temperature, stirred for 0.5 h at room temperature, poured into water and extracted with ether. The extracts were combined washed sequentially with saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by flash chromatography on silica gel, 40:1 hexane/ethyl acetate as eluent to give 1-bromo-3-(5-fluoropentyl)benzene as a pale yellow oil, 0.4 g (63% yield); 1H NMR (DMSO-d6) δ 1.3 (m, 2H); 1.6 (m, 4H); 2.5 (t, 2 H); 4.4 (dxt, 2H); 7.2 (m, 2 H); 7.4 (m, 2 H); MS [(+)ESI] m/z=245 [M−H]+.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[N:20]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:28][Si](C(C)(C)C)(C)C)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CCOCC.CO>[CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[N:20]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([OH:28])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCn1nnnc1[C@]1(F)C[C@@]2(c3ccccc3)[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N2Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COCCOCn1nnnc1[C@]1(F)C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.4 %

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-(tert-butyldimethylsilyloxy)-6-fluoro-6-[1-(2-methoxyethoxymethyl)-1H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Description 44a; 4.5 g, 7.7 mmol), 1 M solution of hydrogen chloride in ether (30 ml) and methanol (50 ml) was stirred at room temperature for 90 minutes. The reaction mixture was treated with saturated aqueous NaHCO, and extracted into ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 20-80%) to give the title compound (2.5 g, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=[O:13].[K].C[N:24](C=O)C>>[Br:1][C:2]1[CH:9]=[C:8]([CH2:10][N:24]2[C:12](=[O:13])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1OCc2ccccc21
Reactant: N#Cc1ccc(CBr)cc1Br
Reactant: CN(C)C=O
Agent: [K]
Product: N#Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 25 °C
Yield: 61 %

Procedure:
To a solution of 2-bromo-4-(bromomethyl)benzonitrile (18.0 g, 65.5 mmol) in DMF (60 mL), potassium phthalide (18.2 g, 98.2 mmol) was added, and then the mixture was stirred under reflux for 4 h. The reaction was allowed to cool to room temperature. After removing DMF under reduced pressure, the residue was dissolved in CH2Cl2 (200 mL), and washed with water (50 mL×2). The organic layer was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was recrystallized from toluene and EtOH to give the product, 2-bromo-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (13.5 g, 61%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:10])([CH3:9])[C:3]=1[CH:11]=[O:12].[CH2:13]1[CH2:18]CCCC1.C1(C)C=CC(S(O)(=O)=[O:26])=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)CO.O>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:10])([CH3:9])[C:3]=1[CH:11]1[O:26][CH2:13][CH2:18][O:12]1
Reactant: C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=C(C=O)C(C)(C)C(C)CC1
Solvent: O
Solvent: OCCO
Product: CC1=C(C2OCCO2)C(C)(C)C(C)CC1
Temperature: 25 °C

Procedure:
2,5,6,6-Tetramethyl-cyclohexene carbaldehyde (64/7/29 trans 2-ene/cis 2-ene/1-ene isomers mixture) (1660 g, 10 mol., 1 eq.), ethylene glycol (1240 g, 20 mol., 2 eq.), cyclohexane (1660 g) and p-toluene sulfonic acid monohydrate (7.6 g, 0.04 mol., 0.004 eq.) were loaded altogether in a 10 liter schmizo type reactor equipped with a heating circulator, temperature probe, mechanical stirring device and a Dean-stark apparatus. The biphasic mixture was heated to reflux under vigorous stirring with azeotropic water removal from reaction mixture. After 8 hours reflux the reaction was then cooled down to room temperature. After decantation of the bottom phase containing excess ethylene glycol and p-toluene sulfonic acid the upper phase was concentrated under vacuum in order to remove cyclohexane and crude 2-(2,5,6,6-tetramethyl-cyclohexenyl)-1,3-dioxolane was obtained in 80% GC purity as a 80/7/13 trans 2-enyl/cis 2-en/1-enyl isomers mixture. Flash distillation afforded 1940 g of 2-(2,5,6,6-tetramethyl-cyclohexenyl)-1,3-dioxolane along with 60 g of residual heavy by-products formed during the reaction.
Reaction SMILES: Br[C:2]1[C:23]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.Br[CH2:31][C:32]#[CH:33].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(#N)C>[CH3:20][C:6]1([CH3:21])[C:7]2[NH:8][C:9]3[C:14](=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=3)[C:15]=2[C:16](=[O:17])[C:4]2[CH:3]=[C:2]([C:33]#[C:32][CH2:31][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:23]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][C:5]1=2
Reactant: CC1(C)c2cc(N3CCOCC3)c(Br)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: C1COCCN1
Reactant: C#CCBr
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC1(C)c2cc(N3CCOCC3)c(C#CCN3CCOCC3)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 9-bromo-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound F3-4, 30 mg, 0.067 mmol), 3-bromopropyne (0.01 ml, 0.13 mmol), morpholine (0.029 ml, 0.33 mmol), X-Phos (4.8 mg, 15% mol), PdCl2 (CH3CN)2 (0.9 mg, 5% mol) and cesium carbonate (87 mg, 0.27 mmol), acetonitrile (2 ml) was added and the mixture was stirred at 80° C. for 2 hr. The reaction solution was added to water, and then extracted with dichloromethane. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (dichloromethane/methanol) to obtain the target compound (pale brown solid, 18 mg, 64%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([F:36])[CH:28]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([F:36])[CH:28]=4)[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCN(c4ccc(C(=O)O)c(F)c4)CC3)cc2)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidin-1-yl}-2-fluoro-benzoic acid was synthesized from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 4-bromo-2-fluoro-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C29H32N2O3 (m/e) 456, obsd 457 (M+H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)([O-])=O.O.NN>CO.[Pd]>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(Nc2ccccc2N)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of methyl 4-[(2-nitrophenyl)amino]benzoate (20 g, 48 mmol) in methanol under nitrogen was treated with 5% Pd/C (1.8 g, 30 w/v) and hydrazine hydrate (11.7 g, 230 mmol), heated at reflux temperature for 2 h, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resultant residue was partitioned between CH2Cl2 and water. The organic phase was separated, dried over Na2SO4 and concentrated under vacuum. The resultant residue was purified with flash column chromatography with (silica, EtOAc:hexanes 4:6) to give 4-(2-aminophenylamino)benzoic acid methyl ester in 80% yield, 1H NMR (400 MHz, CDCl3): 7.87 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.0 Hz, 1H) 7.09 (t, J=8 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.78 (t, J=8 Hz, 1H), 6.67 (d, J=8.0 Hz, 2H), 5.4 (bs, 1H), 3.8 (s, 3H), 3.71 (s, 2H); LCMS (ESI+) 243 (MH+).
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:18]([Cl:31])[CH:17]=1)=[O:4].Cl.C[NH:34]OC.[Cl-].[NH4+].O.[O:40]1[CH2:44]CC[CH2:41]1>>[CH3:41][O:40][CH2:44][NH:34][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:18]([Cl:31])[CH:17]=1)=[O:4]
Reactant: COC(=O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: CNOC
Reactant: C1CCOC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COCNC(=O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reaction time: 0.33 h

Procedure:
In tetrahydrofuran (230 ml) was dissolved 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-quinazoline-6-carboxylic acid methyl ester (X-1, 11.6 g), N,O-dimethylhydroxylamine hydrochloride (7.8 g) was added, and 2 mol/L iPrMgCl tetrahydrofuran solution (79.8 ml) was added dropwise over 30 minutes under ice cooling. After completion of addition, the mixture was stirred for 20 minutes under ice cooling and, after completion of the reaction, 200 ml of aqueous saturated ammonium chloride solution was added. After 100 ml of water was added to the mixture, the mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. The filtrate was concentrated to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-quinazoline-6-carboxylic acid methoxy methyl amide (XI-1, 12.7 g) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:19][C@H:20]([OH:32])[C:21]1[C:29]2[S:28][C:27](=[O:30])[NH:26][C:25]=2[C:24]([OH:31])=[CH:23][CH:22]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].FC(F)(F)C(O)=O.[F:40][C:41]([F:56])([F:55])[C:42]([N:44]1[CH2:49][C:48]2([CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[O:47][CH2:46][CH2:45]1)=[O:43].C(N(CC)CC)C>CC#N>[OH:32][C@H:20]([C:21]1[C:29]2[S:28][C:27](=[O:30])[NH:26][C:25]=2[C:24]([OH:31])=[CH:23][CH:22]=1)[CH2:19][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:52]1[CH2:53][CH2:54][C:48]2([O:47][CH2:46][CH2:45][N:44]([C:42](=[O:43])[C:41]([F:40])([F:55])[F:56])[CH2:49]2)[CH2:50][CH2:51]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCBr)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCCCCCCCCN1CCC2(CC1)CN(C(=O)C(F)(F)F)CCO2)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of (R)-tert-butyl 9-bromononyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)carbamate (example 183-222, step b) (1.68 g) in MeCN (8 mL) was added dropwise to a solution of 2,2,2-trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate (example 12, step d) (1.18 g) and triethylamine (0.81 mL) in MeCN (8 mL). The resulting mixture was stirred at 80° C. for 18 h. The reaction was allowed to cool to RT and the solvent was removed in vacuo. The brown residue was taken up in DCM and the organic layer was washed with water (×2) and brine, dried over sodium sulphate, filtered and evaporated in vacuo. The brown foam was purified by silica gel chromatography eluting with 0-10% MeOH/DCM to give the subtitled compound as a white solid. Yield 500 mg.
Reaction SMILES: N(C(CCCCCCCCCCCCCCCCC)=O)[C@H]([C:4]([NH:6][C@@:7](OCC1C=CC=CC=1)([C:13]([O:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][C:17]1=[O:18])=[O:14])[CH2:8]CC(=O)O)=[O:5])C.[CH2:50](N(CC)CC)C.C(OCC)(=O)C.[CH3:63][C:64]([CH3:66])=[O:65].O>CC(C)=O>[NH:6]([C:4]([O:65][C:64]([CH3:50])([CH3:66])[CH3:63])=[O:5])[C@@H:7]([C:13]([O:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][C:17]1=[O:18])=[O:14])[CH3:8]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@@](CCC(=O)O)(OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reaction time: 8 h

Procedure:
To a solution of Boc-(D)-mesoDAP-(L)-D-AlaOH-(D)-NHNHBoc (2) (2.76 g) and triethylamine in aceton-water (2:1, 90 ml) was added a solution of O-acetylbenziloyl-γ-D-Glu(α-OBzl)-1-succinimidyl ester (3.4 g:5.8 mM) in acetone at 0° C. with stirring. Stirring was continued overnight, allowing the temperature of the mixture to reach to room temperature. After evapolation of acetone, the residue was added ethyl acetate (60 ml), and the organic layer was washed with dil sodium bicarbonate, saturated sodium chloride, dil hydrochloric acid and water. After drying over magnesium sulfate, the solvent was removed in vacuo and triturated with isopropyl ether to give O-acetylbenziloyl-γ-D-Glu(α-OBzl)-(L)-Boc-(D)-mesoDAP-(L)-D-AlaOH-(D)-NHNHBoc (3) (4.63 g).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:47]([NH:54][NH2:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCN(CC)CC>>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([C:16]([NH:55][NH:54][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:18])[CH:13]([CH3:14])[CH3:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NNCc1ccccc1
Yield: 66 %

Procedure:
The general procedure for the preparation of hydrazides described above was followed using Cbz-(L)-valine (0.540 g, 2.15 mmol), EDAC (0.450 g, 2.35 mmol), HOBT (0.320 g, 2.37 mmol), NMM (0.260 mL, 2.36 mmol), benzylhydrazine×2HCl (0.500 g, 2.56 mmol) and Et3N (0.710 mL, 5.09 mmol) which gave the title compound (0.502 g, 66%) as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[CH2:19]([NH2:21])[CH3:20]>COCCOC>[CH2:19]([NH:21][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12])[CH3:20]
Reactant: CCN
Reactant: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])c(F)c2)S1
Solvent: COCCOC
Product: CCNc1cc(C=C2SC(=O)NC2=O)ccc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
5-(3-Fluoro-4-nitro-benzylidene)-thiazolidine-2,4-dione (200 mg, 0.75 mmol, 1 eq.), was dissolved in DME (6 mL) and TEA (208 μL, 1.5 mmol, 2 eq.) and a solution of ethylamine (2 eq.) was added. The reaction mixture was shaken at 60° C. over night. The solvent was removed in vacuo and residue dissolved in ethyl acetate and washed with 10% ammonium chloride aqueous solution. The organic layer was dried on Na2SO4 and the solvent evaporated to give the corresponding aniline derivative as either red oil, which was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:15](Cl)(=[O:19])[C:16](Cl)=O.[CH3:21][N:22]([CH3:25])C=O>ClCCl>[CH2:25]([N:22]([CH2:21][CH:10]([O:19][CH2:15][CH3:16])[O:9][CH2:1][CH3:2])[C:12](=[O:14])[CH2:11][CH2:10][O:9][CH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCOCCc1ccccc1
Reactant: CN(C)C=O
Solvent: ClCCl
Product: CCOC(CN(Cc1ccccc1)C(=O)CCOCCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Phenethyloxypropanoic acid (0.4 g) was dissolved in dichloromethane (10 mL) and treated with oxalyl chloride (0.35 g) and a drop of dimethylformamide at ambient temperature. The resultant solution was stirred at ambient temperature for 1 hour. The solution was then concentrated and azeotroped with dichloromethane (3×10 mL). The collected residue was dissolved in dichloromethane (5 mL) and added, portionwise, to a stirred solution of N-benzyl-2,2-diethoxy-ethanamine (0.47 g) and N-ethyl-N-isopropyl-propan-2-amine (0.6 mL), dissolved in dichloromethane (10 mL), at ambient temperature. The resultant solution was stirred at ambient temperature for 1 hour. The mixture was then poured into ethyl acetate (25 mL), washed with water (2×25 mL), washed with brine (25 mL), dried over anhydrous magnesium sulphate, filtered and concentrated to give the sub-titled compound (0.62 g) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[S:17][C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[S:17][C:16]([S:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:20])=[O:19])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: NCCCCCCCC(=O)O
Product: O=C(O)CCCCCCCNS(=O)(=O)c1ccc(Cl)s1

Procedure:
8-Aminocaprylic acid (1.0 g, 0.006 mole) was treated with 5-chloro-2-thiophene sulphonyl chloride (1.37 g, 0.0063 mole) according to the method described in Example 4 to give the title compound after recrystallisation from isopropanol/water (1.39 g, m.p. 108°-9° C.).
Reaction SMILES: [CH3:1][OH:2].[CH2:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>[Pd]>[CH2:1]([OH:2])/[CH:8]=[CH:3]\[CH2:4]/[CH:5]=[CH:3]\[CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: CO
Reactant: C1CCCCC1
Agent: [Pd]
Product: CCCCC/C=C\C/C=C\CO
Yield: 95 %

Procedure:
6.2 G (37.8 mmole) of the carbinol obtained as indicated under letter i. above, dissolved in 50 ml of cyclohexane, were hydrogenated at atmospheric pressure in the presence of 120 mg of Lindlar type palladium catalyst. After filtration and evaporation, the obtained residue was chromatographed on a silica column, using as eluting agent a mixture of 1 to 10% ethyl acetate in cyclohexane, to give 5.9 g (yield: 95%) of undeca-2Z,5Z-dienol.
Reaction SMILES: [C:1]1([C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[Cl:20][CH2:21][CH:22]([OH:37])[CH2:23][N:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2>CC(C)CC(=O)C>[ClH:20].[CH:26]1[C:25]2[N:24]([CH2:23][CH:22]([OH:37])[CH2:21][N:10]3[CH2:11][CH2:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([OH:13])[CH2:8][CH2:9]3)[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: OC(CCl)Cn1c2ccccc2c2ccccc21
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cl
Product: OC(CN1CCC(O)(c2ccccc2)CC1)Cn1c2ccccc2c2ccccc21
Yield: 60.8 %

Procedure:
4-Phenylpiperidin-4-ol (0.77 g, 0.0043 mol) was dissolved in 4-methyl-pentan-2-one (40 mL), K2CO3 (1.59 g, 0.0116 mol) and 9-(3-chloro-2-hydroxy-1-propyl)carbazole (0.75 g, 0.0029 mol) were added, and the resulting mixture was stirred at reflux temperature overnight. The reaction mixture was filtered and the solvent was removed in vacuo. The residual oil was purified on a silica gel column (Eluent: CH2Cl2 /ethanol/25% NH4OH (aq) (92.75:7:0.25)), and further purified on a silica gel column (Eluent: Gradient 1) ethyl acetate/methanol (20:1); 2) ethyl acetate/methanol (3:1); 3) CH2Cl2 /methanol (9:1)). The product was acidified with 2M HCl(g) in diethyl ether, to give the title compound 0.77 g (61%). M.p. decomposes at 193-224° C.