Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[N:9]=[C:8]([CH3:12])[C:7]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:6]=3[C:5]=2[C:4](=O)[CH2:3]1.N1C=CC=CC=1.Cl.[NH2:28][OH:29]>C(O)C>[CH3:1][CH:2]1[CH2:11][C:10]2[N:9]=[C:8]([CH3:12])[C:7]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:6]=3[C:5]=2[C:4](=[N:28][OH:29])[CH2:3]1
Reactant: NO
Reactant: Cc1nc2c(c3c1[nH]c1ccccc13)C(=O)CC(C)C2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1nc2c(c3c1[nH]c1ccccc13)C(=NO)CC(C)C2
Yield: 60.9 %

Procedure:
A mixture of 3,6-dimethyl-2,3,4,7-tetrahydroindolo[2,3-c]quinolin-1-one of Example 12 (0.26 g, 1 mmol), ethanol (4 mL), pyridine (0.15 mL, 1.85 mmol) and hydroxylamine hydrochloride (0.1 g, 1.5 mmol) was refluxed for 3 h. The mixture was cooled, the solid product was filtered off, washed with ethanol, dried, and dissolved in hot water (20 mL). Aqueous ammonium hydroxide was added to pH 9. The precipitate was collected, washed with water, dried and crystallized from ethanol-water, 1:1 to give 0.17 g (61%) of colorless crystals; m.p. 282-283° C.
Reaction SMILES: FC(F)(F)C(F)=C(F)F.[F:10][C:11]([F:28])([F:27])[CH:12]([C:17](F)([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:13]([F:16])([F:15])[F:14].S(=O)(=O)(O)[OH:30]>O>[F:10][C:11]([F:28])([F:27])[C:12]([OH:30])([CH:17]([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:13]([F:16])([F:15])[F:14]
Reactant: O=S(=O)(O)O
Reactant: FC(F)(F)C(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Agent: FC(F)=C(F)C(F)(F)F
Solvent: O
Product: OC(C(F)C(F)(F)C(F)(F)F)(C(F)(F)F)C(F)(F)F

Procedure:
To prepare 2-trifluoromethyl-1,1,1,3,4,4,5,5,5-nonafluoro-2-pentanol, commercially available hexafluoropropene may be oligomerized with commercially available trimethylamine in a dipolar aprotic solvent such as commercially available tetrahydrofuran to provide (CF3)2C:CFCF2CF3 which is then reacted with commercially available hydrogen fluoride to yield 2-trifluoromethyl-1,1,1,3,3,4,4,5,5,5-decafluoropentane as taught by W. Brunskill et al., "Anionic Oligomerisation of Hexafluoropropene: Fission of a Carbon-Carbon Bond by Fluoride Ion", Chemical Communications, 1444 (1970). The 2-trifluoromethyl-1,1,1,3,3,4,4,5,5,5-decafluoropentane may then be dehydrohalogenated and then reacted with sulfuric acid and then water to form 2-trifluoromethyl-1,1,1,3,4,4,5,5,5-nonafluoro-2-pentanol.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:37]=[CH:38][C:39]([CH3:42])=[N:40][CH:41]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[C:10]2[N:9](/[CH:33]=[C:34](/[C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][CH:37]=3)\[CH3:35])[C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=CBr)c1ccc(C)nc1
Reactant: CN1CCc2[nH]c3c(Cl)cccc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cccc(Cl)c31)CN(C)CC2)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (203 mg, 0.8 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (19 mg, 0.10 mmol), L-proline (23 mg, 0.20 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 5-(1-Bromoprop-1-en-2-yl)-2-methylpyridine (212 mg, 1 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). The product was further purified by HPLC. 1H NMR (CDCl3, TFA salt) δ (ppm): 9.10 (s, 1H), 8.20 (d, 1H), 7.60 (d, 1H), 7.30 (m, 2H), 7.20 (d, 1H), 7.10 (t, 1H), 4.75 (m, 1H), 4.18 (m, 1H), 3.90 (m, 1H), 3.30 (m, 2H), 3.05 (s, 3H), 2.90 (m, 1H), 2.80 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[N:8]=[CH:7]2)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[N:15]1([CH2:14][CH2:13][N:9]2[C:10]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=3)[CH:7]=[N:8]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2CCN2CCCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-Nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole (3.00 g, 11.5 mmol), iron powder (6.50 g, 116 mmol), and ammonium chloride (310 mg, 5.85 mmol) in a 4:1 mixture of ethanol/H2O was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes, filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.62 (m, 4H), 2.44 (m, 4H), 2.81 (t, 2H, J=6.78), 4.36 (t, 2H, J=6.78), 4.77 (s, 2H), 6.72 (m, 1H), 6.79 (m, 1H), 7.35 (m, 1H), 7.68 (s, 1H); MS (DCI/NH3) m/z 231 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][Si:4](Cl)(Cl)Cl.C([O:11][C:12](=[O:14])[CH3:13])(=O)C>>[Cl:1][CH2:2][CH2:3][Si:4]([O:11][C:12](=[O:14])[CH3:13])([O:14][C:12](=[O:11])[CH3:13])[O:14][C:12](=[O:11])[CH3:13]
Reactant: ClCC[Si](Cl)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)O[Si](CCCl)(OC(C)=O)OC(C)=O
Reaction time: 21 h
Yield: 80.5 %

Procedure:
An amount of 40.8 g of 2-chloroethyl-trichlorosilane is dissolved in 71.5 g of acetic acid anhydride, and the solution allowed to stand at room temperature for 21 hours in a closed vessel. The reaction product is concentrated in vacuo to obtain 44.6 g of 2-chloro-ethyl-tris-(acetyloxy)-silane, B.P.: 85° - 88°/0.1 Torr, nD20 = 1.6687. b) An amount of 26.9 g of 2-chloroethyl-tris-(acetyloxy)silane is dissolved in 40 ml of absolute benzene. To the solution are added at 50° - 55°, within 60 minutes, 10.8 g of benzyl alcohol in 20 ml of absolute benzene. Stirring is carried out for 41/2 hours at 50° - 55°. The reaction mixture is concentrated in vacuo, and 14.3 g of 2-chloroethyl-(benzyloxy-diacetyloxy)-silane are obtained, B.P.: 125 - 127°/0.001 Torr, nD20 = 1.4840. (Compound 1).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=1.O>CN(C)C=O>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:1][C:2]2[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)=[CH:19][CH:20]=3)[N:3]=2)[CH:25]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1O
Reactant: ClCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3)cc2)nc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (435 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 120 mg) was added at 0° C., and then the solution was stirred at room temperature for 30 minutes. 3-Picolyl chloride (574 mg) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-(3-pyridylmethoxy)-1-[4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (533 mg, yield: 75%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:7][CH:8]=1
Reactant: COc1ccc(C=CCCCCCC(=O)O)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: COc1ccc(CCCCCCCC(=O)O)cc1
Yield: 95.9 %

Procedure:
This compound was synthesized from 8-(p-methoxyphenyl)-7-octenoic acid (1.24 g, 5 mmol) and Pd/BaSO4 (125 mg) by hydrogenation. Crystallization (petroleum ether) afforded the product (1.20 g, 96%) as white crystals (mp 42-43° C.). IR: 3400-2500, 1705 cm-1 ; 1H-NMR: 1.40 (m, 10H), 2.40 (m, 4H), 3.80 (s, 3H), 6.95 (q, 4H), 10.10 (bs, 1H). Anal. Calcd. for C15H22O2 : C, 71.97, H, 8.86%; Found: C, 72.07, H, 8.88%.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[NH:4][CH2:5][C:6]([C:8]1[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH:10]=[CH:11][CH:12]=1)=[O:7].[BH4-].[Na+].CO.O>C(O)(C)C>[CH:2]1([NH:4][CH2:5][CH:6]([C:8]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:10]=[CH:11][CH:12]=2)[OH:7])[CH2:3][CH2:1]1
Reactant: O=C(CNC1CC1)c1cccn1Cc1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: OC(CNC1CC1)c1cccn1Cc1ccccc1F
Temperature: 85 °C

Procedure:
A solution of 8.0 g of 2-(2-cyclopropylamino)acetyl-1-(o-fluorobenzyl)pyrrole, free base of a, in 100 ml of isopropyl alcohol is added to a suspension of 2.2 g sodium borohydride in 100 ml of isopropranol. The reaction mixture is refluxed at 85° C. for 4 hours, allowed to cool to ambient temperature and 50 ml of methanol introduced. The solvent is removed leaving a yellow semi-solid which is treated with water and then extracted into ether. The ether extract is washed with water, dried and filtered and the solvent removed leaving a pure yellow oil of 2-(cyclopropylamino)-1-[1-(o-fluorobenzyl)-2-pyrryl]ethanol. Infrared and nuclear magnetic resonance spectra confirm this structure.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=O)=O.[I-:18].[Na+].O>CC(C)=O>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH2:7][CH2:6][I:18]
Reactant: [I-]
Reactant: COc1ccc(CCOS(C)(=O)=O)cc1OC
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(CCI)cc1OC
Yield: 92.6 %

Procedure:
To a flask was added 21.2 g (0.078 mole) of 2-(3,4-dimethoxyphenyl)ethyl methanesulfonate and 44.65 g (0.3 mole) of sodium iodide in 420 ml of acetone. The solution was refluxed for 2 hr, poured into water, washed with brine, dried over MgSO4, and evaporated to give 21.1 g of a yellow oil. The oil was recrystallized in MeOH to give 17.1 g of product, mp 43°-46° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]2[CH:13]3[O:14][CH:12]3[C:11]([CH3:16])([CH3:15])[O:10][C:9]=2[CH:17]=1)(=[O:3])[CH3:2].[NH3:21]>C(O)C>[C:1]([NH:4][C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]2[C@@H:13]([NH2:21])[C@H:12]([OH:14])[C:11]([CH3:16])([CH3:15])[O:10][C:9]=2[CH:17]=1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])C1OC1C(C)(C)O2
Solvent: CCO
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])[C@@H](N)[C@H](O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
7-Acetamido-3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran (0.76 g,) was dissolved in dry ethanol and saturated with dry ammonia, and stirred at room temperature for 21 hr. Evaporation gave a crude mixture which was purified on the chromatotron (using pentane-ethyl acetate in a gradient elution), to give the title compound (280 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:8]2)([O-:3])=[O:2].[H-].[Na+].CI.[C:22](=O)([O-])O.[Na+]>O1CCCC1>[CH3:22][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[C:7]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a stirred solution of ethyl 4-nitroindole-2-carboxylate (1.57 g, 6.70 mmol) in anhydrous tetrahydrofuran (20 mL) at 0° C. under nitrogen was added sodium hydride (60% in oil, 0.375 g, 9.4 mmol, 1.4 equivalents), and the resulting effervescing mixture was stirred at room temperature under nitrogen for 30 minutes. Then, methyl iodide (1.71 g, 12.0 mmol, 1.8 equivalents) was added dropwise, and the resulting reaction solution was stirred at room temperature under nitrogen for 48 hours. A saturated solution of sodium hydrogen carbonate was then added, and the resulting aqueous mixture was extracted with ethyl acetate (2×30 mL). The organic extracts were combined, dried (sodium sulfate), and evaporated under reduced pressure. The residue was chromatographed using silica gel (approximately 50 g) and elution with 20% ethyl acetate in hexanes to afford the title compound (0.35 g, 1.41 mmol, 21%) as a yellow solid: Rf=0.30 in 20% ethyl acetate in hexanes; 1H NMR (acetone-d6) δ8.18 (d, J=7.9 Hz, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.78 (s, 1H), 7.57 (t, J=8.1 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 4.21 (s, 3H), 1.42 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([Li])[CH2:10]CC>>[OH:8][C:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: [Li]CCCC
Product: OC1=CCc2ccccc21

Procedure:
Alternatively, compounds of formula I can be prepared as shown in Scheme 10. A benzaldehyde derivative 7-1 can be alkylated by treatment with n-butyllithium in the presence of N,N,N′-trimethylethane-1,2-diaminene followed by quenching with acrolein. The resulting semiacetal 10-1 can be converted to an olefin by treating with Ph3PCH3Br/n-butyllithium. Cyclization using Grubbs catalyst gives rise to 3-hydroxyindene derivative 10-3 which can be subjected to an oxidation using an oxidant such as pyridinium chlorochromate (PCC). Michael addition of intermediate 8-5 to the resulting ketone 10-4 affords intermediate 10-5. Following reduction of the ketone to alcohol, alkylation with R9I can be accomplished using a base such as sodium hydride. Removal of Boc followed by coupling with R1CO2H using a coupling agent such as EDCI/HOBt affords compounds of formula 10-7.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]2([C:42]3[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=3)[CH2:41][CH2:40]2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>>[OH:31][C:30]1[C:25](=[O:24])[NH:26][N:27]=[C:28]([C:39]2([C:42]3[CH:47]=[CH:46][C:45]([C:48]([F:50])([F:49])[F:51])=[CH:44][CH:43]=3)[CH2:40][CH2:41]2)[CH:29]=1
Reactant: FC(F)(F)c1ccc(C2(c3cc(OCc4ccccc4)c(OCc4ccccc4)nn3)CC2)cc1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Product: O=c1[nH]nc(C2(c3ccc(C(F)(F)F)cc3)CC2)cc1O
Yield: 20 %

Procedure:
Prepared in the same manner as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{1-[4-(trifluoromethyl)phenyl]-cyclopropyl}-pyridazine (Intermediate 68) in 20% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Si](C)(C)C.C(N(CC)C(C)C)(C)C.[CH:34]1[C:44]2[CH2:43][CH2:42][C:41]3[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=3[N:39]([C:49](Cl)=[O:50])[C:38]=2[CH:37]=[CH:36][CH:35]=1>>[CH:34]1[C:44]2[CH2:43][CH2:42][C:41]3[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=3[N:39]([C:49]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:12][C@H:13]3[C:17]([OH:19])=[O:18])=[O:50])[C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)N1c2ccccc2CCc2ccccc21
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)N1c2ccccc2CCc2ccccc21
Yield: 23.4 %

Procedure:
Following the procedure of Example 16, Step B, 811 mg (2.5 mmole) of (S)-4-(benzyloxycarbonyl)-piperazine-2-carboxylic acid (from Example 7, Step A) 680 mg (6.26 mmole) of chlorotrimethylsilane, 1.23 g (9.5 mmole) of N,N-diisopropylethylamine and 665 mg (2.5 mmole ) of 97% of 10,11-dihydro-5H-dibenz[b,f]-azepine-5-carbonyl chloride , gave 284 mg (24%) of (S)-1-(10,11-dihydro-5H-dibenz [b,f]azepine-5-carbonyl)-4-(benzyloxycarbonyl)piperazine-2-carboxylic acid, mp 185° C. (softened >90° C.); TLC Rf 0.68 (Antaltech SGF plates developed with isoamyl alcohol:acetone:water [5:2:1]).
Reaction SMILES: [CH3:1][C:2](=[CH2:49])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:48])[C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][O:32][C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43][CH3:44])=[O:42])=[CH:35][C:34]=2[O:45][CH3:46])[CH:22]=[CH:21][C:20]=1[OH:47])=[O:4].[CH2:50]([C:55]1[CH:63]=[CH:62][C:58]([C:59](O)=[O:60])=[CH:57][CH:56]=1)[CH2:51][CH2:52][CH2:53][CH3:54].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:49][C:2](=[CH2:1])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:48])[C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][O:32][C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43][CH3:44])=[O:42])=[CH:35][C:34]=2[O:45][CH3:46])[CH:22]=[CH:21][C:20]=1[O:47][C:59](=[O:60])[C:58]1[CH:62]=[CH:63][C:55]([CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:56][CH:57]=1)=[O:4]
Reactant: C=C(C)C(=O)OCCCCCCCCCCCOC(=O)c1cc(CCCCCCOOc2ccc(/C=C/C(=O)OC)cc2OC)ccc1O
Reactant: CCCCCc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCCCCCCOC(=O)c1cc(CCCCCCOOc2ccc(/C=C/C(=O)OC)cc2OC)ccc1OC(=O)c1ccc(CCCCC)cc1
Yield: 78.2 %

Procedure:
1.43 g (2.09 mmol) (E)-2-hydroxy-5-[6-[2-methoxy-4-(methoxycarbonylvinyl)phenoxy]oxyhexyl]benzoic acid 11-(2-methylacryloyloxy)undecyl ester, 0.42 g (2.20 mmol) 4-pentylbenzoic acid and 64 mg (0.52 mmol) 4-dimethylaminopyridine were dissolved in 30 ml of dichloromethane. A suspension of 0.42 g (2.20 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 3 ml dichloromethane were added dropwise in the course of 15 minutes. After 20 hour at room temperature the reaction mixture was partitioned between dichloromethane and water; the organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 150 g silica gel using cyclohexane:ethyl acetate 4:1 and subsequent crystallisation form 20 ml isopropyl alcohol yielded 1.40 g (78%) (E)-2-[4-pentylbenzoyloxy]-5-[6-[2-methoxy-4-(methoxycarbonylvinyl)phenoxy]oxyhexyl]benzoic acid 11-(2-methylacryloyloxy)undecyl ester as white crystals.
Reaction SMILES: C(O[C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[CH:14]([NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([Cl:25])[CH:19]=1)[CH3:15])=[O:7])(C)(C)C.[O:28]=[C:29]1[O:33][CH:32]([O:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39]C=2)[CH:31]([NH:43]C(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)[CH2:30]1>>[CH:36]1([CH2:35][O:34][CH:32]2[CH:31]([NH:43][C:6]([CH:8]3[CH2:12][CH2:11][CH2:10][N:9]3[C:13](=[O:27])[CH:14]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([Cl:25])[CH:19]=3)[CH3:15])=[O:7])[CH2:30][C:29](=[O:28])[O:33]2)[CH2:37][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCC1CCCCC1
Yield: 56 %

Procedure:
Prepared from 97a and syn-(2-cyclohexylmethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 113 mg (56% yield) of the title compound. 1H-NMR (500 MHz, CDCl3): δ 0.70-1.35 (m, 5H), 1.35-1.90 (m, 8H), 1.90-2.20 (m, 3H), 2.30-2.60 (m, H), 2.80-3.00 (m, H), 3.15-3.80 (m, 4H), 4.28-4.75 (m, 4H), 4.89-4.93 (m, H), 5.42 (d, H), 6.74 (d, H), 6.87 (d, H), 7.30 (d, H), 7.51-7.53 (m, H), 7.74 (d, H); retention time on analytical HPLC: 12.02 min; LC-MS: m/z=535 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15]([C:17]1[C:21]([NH2:22])=[CH:20][NH:19][N:18]=1)=[O:16])[CH3:13].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:12]([O:14][C:15]([C:17]1[C:21]([NH:22][C:4](=[O:6])[C:3]2[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[CH:20][NH:19][N:18]=1)=[O:16])[CH3:13]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: CCOC(=O)c1n[nH]cc1N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2,6-difluorobenzoic acid (6.32 g, 40.0 mmol), 4-amino-1H-pyrazole-3-carboxylic acid ethyl ester (5.96 g, 38.4 mmol), EDC (8.83 g, 46.1 mmol) and HOBt (6.23 g, 46.1 mmol) in DMF (100 ml) was stirred at ambient temperature for 6 h. The mixture was reduced in vacuo, water added and the solid formed collected by filtration and air-dried to give 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid ethyl ester as the major component of a mixture (15.3 g). (LC/MS: Rt 3.11, [M+H]+ 295.99).
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([O:36]C)=[O:35])[CH2:30][CH2:29]3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+]>C1COCC1.O>[C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26]([N:28]3[CH2:29][CH2:30][CH:31]([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]3)=[O:27])[CH2:11]2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CCN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(C(=O)O)CC2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
27 mg (0.05 mmol) of methyl 1-({3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)piperidine-4-carboxylate were initially charged in 0.8 ml each of THF and water, and 4 mg (0.15 mmol) of lithium hydroxide were added. The mixture was stirred at RT overnight. The reaction solution was concentrated under reduced pressure and acidified, and the precipitate was filtered off and dried. Yield: 16 mg (62% of theory)