Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][O+:7]([CH3:9])C.CO[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[N:13]=1.N1C=CC=CC=1.F[B-](F)(F)F>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:12][N:13]1[C:6]([O:7][CH3:9])=[CH:17][CH:16]=[CH:15][CH:14]1[CH:18]=[O:19]
Reactant: COc1cccc(C=O)n1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1=CC=CC(C=O)N1C

Procedure:
A 3 mL glass vial was equipped with a rubber septum and magnetic stir bar. The vial was brought into a glove box and charged with trimethyloxonium tetrafluoroborate (198 mg, 1.33 mmol). The vial was sealed and removed from the glove box. A separate 3 mL vial was charged with 2-methoxy-6-pyridinecarboxaldehyde (Aldrich #662933, 184 mg, 1.34 mmol) and was dissolved in CH2Cl2 (1.5 mL). The solution of pyridine was added via syringe onto the solid trimethoxonium tetrafluoroborate at room temperature. The vial which contained the pyridine was rinsed with CH2Cl2 (1 mL) and the rinse solution was injected into the reaction vial. The reaction vial was kept at room temperature and stirring was maintained at ca. 400-600 rpm. Over the course of the reaction (17 h), the solid trimethoxonium tetrafluoroborate gradually dissolved, the solution clarified, and an oil gradually formed. At the end of the reaction, hexanes (2 mL) were added after which stirring was stopped. Any solid or oil was allowed to settle and the solvent was removed by glass pipette. The solid or oil was then rinsed with several portions of hexanes followed by diethyl ether. Residual solvent was then removed in vacuo to provide the compound N-methyl-6-methoxy-2-pyridinecarboxaldehyde tetrafluoroborate. This oil was used for oxime formation without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH:27]4[CH2:31][CH2:30][CH2:29][O:28]4)=[O:24])[C:5](=[O:32])[N:4]3[CH2:3][CH2:2][NH:1][S:43]([CH3:42])(=[O:45])=[O:44])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-(tetrahydro-2-furanylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with methanesulfonyl chloride (0.0053 mL, 0.068 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH, and dried in vacuo to provide the title compound as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44-1.67 (m, 1 H), 1.80-1.89 (m, 3 H), 2.90 (s, 3 H), 3.19-3.29 (m, 2 H), 3.34-3.41 (m, 1 H), 3.53-3.61 (m, 1 H), 3.64-3.71 (m, 1 H), 3.77-3.87 (m, 1 H), 3.97-4.08 (m, 1 H), 4.14 (s, 2 H), 4.35 (t, J=6.18 Hz, 2 H), 7.10-7.18 (m, 2 H), 7.26 (t, J=5.76 Hz, 1 H), 7.40 (dd, J=8.14, 5.48 Hz, 2 H), 8.11 (s, 1 H), 8.55 (s, 1 H), 10.39 (t, J=5.97 Hz, 1 H), 17.10 (s, 1 H); ES+ MS: 519 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:24][NH2:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:17]([O:16][C:14](=[O:15])[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:24][NH2:25])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CN)CCCCNC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC[C@@H](N)CCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of ((S)-1-aminomethyl-5-benzyloxycarbonylamino-pentyl)-carbamic acid tert-butyl ester (0.24 g, 0.657 mmol) in DCM (2.4 ml) is treated dropwise with TFA (0.6 ml) and stirred at room temperature for 3 days. The solvent is removed in vacuo to afford ((S)-5,6-Diamino-hexyl)-carbamic acid benzyl ester as a yellow oil; [M+H]+ 266
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[CH:8]=[CH:7][CH:6]=[CH:5]2.Cl[C:12]([O:14][CH3:15])=[O:13]>>[CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: COC(=O)Cl
Reactant: Cc1cc2ccccn2c1
Product: COC(=O)c1c(C)cc2ccccn12
Yield: 72.9 %

Procedure:
A mixture of 2-methylindolizine 1 (3.8 g, 29.0 mmol) and methyl chloroformate (22 g (18 ml), 231.6 mmol) was heated at reflux for 2 h. A further 12.2 g (10 ml) of methyl chloroformate were added, and the mixture was heated at reflux for 2 h. The reaction mixture was concentrated under vacuum and then purified by chromatography on a silica column (hexane/ethyl acetate 5:1, silica gel 200-425 mesh) to give 4 g of compound 2 (colorless oil). 1H NMR (CDCl3): δ 9.43 (d, J=7.1 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 6.99-6.93 (m, 1H), 6.73-6.68 (m, 1H), 6.29 (s, 1H), 3.91 (s, 3H), 2.53 (s, 3H), 13C NMR (CDCl3): δ 162.7, 137.0, 134.6, 127.6, 121.8, 117.6, 111.8, 103.5, 103.48, 50.6, 15.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC>O1CCCC1>[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](=[O:14])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccncc1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 4-methylpyridine (74.4 g) and ethyl 4-fluorobenzoate (134.4 g) in dry tetrahydrofuran (600 ml) was added a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.6 l) dropwise with ice cooling. The mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture was added hexane (12.2 l) and the separated solid was collected, washed with hexane and dried. The obtained solid was dissolved in 3N-hydrochloric acid (800 ml) and the solution was neutralized with an aqueous saturated sodium bicarbonate solution. The separated solid was collected, washed with water and dried to give 1-(4-fluorophenyl)-2-(pyridin-4-yl)ethan-1-one (148 g).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[SH:34][CH2:35][CH2:36][OH:37]>C(Cl)Cl>[OH:37][CH2:36][CH2:35][S:34][CH:2]1[C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2
Reactant: OCCS
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CC2
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)C(SCCO)c1ccccc1CC2
Temperature: 25 °C

Procedure:
In 15.3 ml of methylene chloride was suspended 0.51 g of methyl 5-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylate. Under ice cooling, 0.27 ml of trifluoroacetic anhydride was added to the suspension followed by stirring at room temperature for an hour. Then, 0.14 ml of 2-mercaptoethanol was added to the mixture followed by stirring for further an hour. After 10 ml of methylene chloride was added to the reaction mixture, the mixture was washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) and recrystallized from toluene to give 0.51 g of the objective compound as light yellow crystals.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[NH2:15][CH2:16][C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:24][C:25]3[N:41]=[C:29]([NH:30][C:31]4[CH:32]=[CH:33][CH:34]=[C:35]([CH:40]=4)[CH2:36][CH2:37][C:38]=1[CH:39]=2)[N:28]=[CH:27][C:26]=3[Cl:42])=[O:18].[C:43]1([N:49]=[C:50]=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:49]([C:50]([NH:15][CH2:16][C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:24][C:25]3[N:41]=[C:29]([NH:30][C:31]4[CH:32]=[CH:33][CH:34]=[C:35]([CH:40]=4)[CH2:36][CH2:37][C:38]=1[CH:39]=2)[N:28]=[CH:27][C:26]=3[Cl:42])=[O:18])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NCC(=O)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)Nc1ccccc1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 38 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using 2-amino-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 38% yield. LCMS for C27H25ClN7O2 (M+H)+: m/z=514.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC1CCN(c2ccncc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(OCC3CCN(c4ccncc4)CC3)ccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.6 %

Procedure:
To a solution of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-Butyl Ester (320 mg) and 4-hydroxymethyl-1-(pyridin-4-yl)piperidine (247 mg) in a mixture of tetrahydrofuran (15 ml) and methylene chloride (5 ml) were successively added triphenylphosphine (370 mg) and diisopropyl azodicarboxylate (0.28 ml), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:acetone=3:2-1:1, 1% triethylamine) and dried under reduced pressure to give the title compound (400 mg).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[F:32]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([F:32])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2F)CC1
Temperature: 40 °C

Procedure:
(R)-4-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.3012 g, 0.0007895 mol) was dissolved in methylene chloride (5.00 mL, 0.0780 mol) in a capped 40 mL vial equipped with a magnetic stir bar. N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (0.249 g, 0.000789 mol) was added followed by zirconium tetrachloride (0.184 g, 0.000789 mol) and the mixture was heated overnight at 40° C. The reaction mixture was cooled to room temperature then concentrated to dryness under reduced pressure, adsorbed onto silica gel and purified by flash chromatography (0-55% EtOAc in hexanes) to give 131.3 mg of the title compound (42% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH:10]([C:21](OC)=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH:10]([CH2:21][OH:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccccc2)CC1CO
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 336a (1 g, 2.99 mmol) in 100 mL of anhydrous tetrahydrofuran was slowly added lithium aluminum hydride (342 mg, 8.98 mmol) at 0° C. and the mixture was stirred for 30 min. Then, it was refluxed for 3 h and the reaction mixture was poured onto ice portionwise. The resulting mixture was filtered and the filtrate was evaporated in vacuo. After addition of 100 mL brine to the residue, it was extracted with methylene chloride (100 mL×3). The combined organic layer was dried over Na2SO4, filtered, and concentrated to afford 336b as yellow oil (0.60 g, 91%). MS: [M+H]+ 221.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].[H-].[Na+].CS([C:15]1[N:16]=[C:17]([O:41][CH2:42][CH2:43][CH3:44])[C:18]2[N:23]=[C:22]([C:24]3[CH:38]=[C:37]([CH3:39])[C:27]([O:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:26]([CH3:40])[CH:25]=3)[O:21][C:19]=2[N:20]=1)(=O)=O>CN(C)C=O>[F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:15]1[N:16]=[C:17]([O:41][CH2:42][CH2:43][CH3:44])[C:18]2[N:23]=[C:22]([C:24]3[CH:25]=[C:26]([CH3:40])[C:27]([O:28][CH2:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[C:37]([CH3:39])[CH:38]=3)[O:21][C:19]=2[N:20]=1
Reactant: O[C@@H]1CCCC[C@H]1F
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Reaction time: 0.25 h

Procedure:
Under an atmosphere of argon and at 0 C, 26 mg of trans-2-fluorocyclohexanol were added to a suspension of 10 mg of sodium hydride (60% in mineral oil) in 2 ml of N,N-dimethylformamide. After 15 min, a solution of 100 mg of tert-butyl [4-(5-methanesulfonyl-7-propoxyoxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate in 1 ml of N,N-dimethylformamide was slowly added. After 12 h at room temperature, the mixture was quenched by addition of water and extracted twice with ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure. This gave 101 mg of the title compound.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:16]([CH2:20][CH2:21][OH:22])[CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][OH:22])[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: OCCNCCO
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Product: O=C(c1ccccc1)c1ccc(N(CCO)CCO)cc1
Temperature: 155 °C
Yield: 61.7 %

Procedure:
A 100 mL two-neck flask was charged with 4-fluorobenzophenone (15.0 g; 74.9 mmol) and diethanolamine (55.1 g; 524 mmol). The flask was flushed with nitrogen, fitted with a reflux condenser and heated to 155° C. for 48 h under a gentle stream of nitrogen. Complete conversion of the starting 4-fluorobenzophenone was confirmed by TLC. After cooling to ambient temperature, the dark viscous reaction mixture was poured into water (2000 mL). The resulting suspension was thoroughly extracted with diethyl ether (6×250 mL). The aqueous phase was discarded and the organic phase was extracted with hydrochloric acid (2M, 5×200 mL). The pH of the strongly acidic aqueous phase was adjusted to 12-13 by slow addition of 35% aq. ammonia to reprecipitate the product. The aqueous phase was then reextracted with dichloromethane (3×300 mL). The crude organic extract was purified by passing through a short silica gel column (eluent: ethyl acetate). The eluted yellow solution was evaporated and the oily residue dried in vacuo to provide {4-[bis(2-hydroxyethyl)amino]phenyl}(phenyl)methanone (yellow-brown solid; 13.176 g; 62% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9]O)[CH:2]=1.[BrH:11]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][Br:11])[CH:2]=1
Reactant: Br
Reactant: OCCCc1cccnc1
Product: BrCCCc1cccnc1

Procedure:
To 17.0 g (124 moles) of 3-(3-pyridyl)-1-propanol was added 240 mL of 48% hydrobromic acid. The mixture was heated under reflux for 4 hours, and then evaporated to dryness to afford the hydrobromide salt of 3-(3-pyridyl)-1-bromopropane as an oil in quantitative yield.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[Cl:27][C:28]1[S:29][C:30]([S:34]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)(=[O:36])=[O:35])=[CH:31][C:32]=1[NH2:33]>>[Cl:27][C:28]1[S:29][C:30]([S:34]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)(=[O:35])=[O:36])=[CH:31][C:32]=1[NH:33][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN1CCN(S(=O)(=O)c2cc(N)c(Cl)s2)CC1
Product: CN1CCN(S(=O)(=O)c2cc(NC(=O)c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)c(Cl)s2)CC1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-chloro-5-(4-methyl-piperazine-1-sulfonyl)-thiophen-3-ylamine (example B.22) according to general procedure II.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)(O)[CH2:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:22]1(/[CH:21]=[C:20](/[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)\[C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1ccc(C(O)(CC2CCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCC2)c2cc3cc(F)cnc3[nH]2)cc1
Yield: 62.1 %

Procedure:
A solution of 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclobutyl-1-(4-methylsulfonyl-phenyl)-ethanol (520 mg, 1 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 5.0 mL, 5.0 mmol) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using a 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 2-[(E)-2-cyclobutyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (230 mg, 62.1%) as a light yellow solid: LC/MS m/e calcd for C20H19FN2O2S [M+H]+ 371.45, observed 371.0; 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (d, J=8.3 Hz, 3H), 7.50-7.58 (m, 3H), 6.66 (d, J=9.3 Hz, 1H), 5.86 (s, 1H), 3.22 (s, 3H), 2.99 (m, 1H), 2.04-2.16 (m, 4H), 1.85-1.94 (m, 2H).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)[CH2:9][CH3:10].S(Cl)([Cl:22])=O>N1C=CC=CC=1>[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([Cl:22])=[O:19])[CH2:13][CH2:12]1)[CH2:9][CH3:10]
Reactant: CCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Toluene (1,000 ml) was added to trans-4-propylcyclohexanecarboxylic acid (1) (500.0 g) in a reaction vessel under an atmosphere of nitrogen, and the mixture was heated to 50° C. Pyridine (0.70 ml) and thionyl chloride (360.0 g) were then added, and the stirring was continued for 3 hours. The unreacted thionyl chloride and the toluene were distilled off at atmospheric pressure. The residue was distilled under reduced pressure (83° C., 3 mmHg) to give trans-4-propylcyclohexanecarboxylic acid chloride (2) (531.7 g) in 98% yield.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[CH3:16].Cl>O1CCCC1>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[CH:19]=[CH:18][C:17]([CH:15]([CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:16])=[CH:22][CH:21]=1)#[N:30]
Reactant: CC(Br)c1ccc(-c2ccccc2C#N)cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(C(=O)OCC)C(C)c1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a mixture of 60% sodium hydride in oil (0.82 g) and tetrahydrofuran (20 mL) was added dropwise a mixture of ethyl 3-oxohexanoate (4.35 g) in tetrahydrofuran (20 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Then, 4′-(1-bromoethyl)biphenyl-2-carbonitrile (3.93 g) was added, and the mixture was stirred at 50° C. overnight. The reaction mixture was poured into 1 M hydrochloric acid (30 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (4.70 g, 94%).
Reaction SMILES: [CH3:1][C:2](=[CH2:42])[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:41])[C:19]1[CH:24]=[C:23]([O:25][C:26](=[O:39])[C:27]2[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]=1[OH:40])=[O:4].[CH2:43]([C:46]1[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][CH:47]=1)[CH2:44][CH3:45].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:42][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:41])[C:19]1[CH:24]=[C:23]([O:25][C:26](=[O:39])[C:27]2[CH:28]=[CH:29][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:32]=2)[CH:22]=[CH:21][C:20]=1[O:40][C:50](=[O:51])[C:49]1[CH:53]=[CH:54][C:46]([CH2:43][CH2:44][CH3:45])=[CH:47][CH:48]=1)=[O:4]
Reactant: CCCc1ccc(C(=O)O)cc1
Reactant: C=C(C)C(=O)OCCCCCCCCCCCOC(=O)c1cc(OC(=O)c2ccc(/C=C/C(=O)OC)cc2)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCCCCCCOC(=O)c1cc(OC(=O)c2ccc(/C=C/C(=O)OC)cc2)ccc1OC(=O)c1ccc(CCC)cc1
Yield: 79.2 %

Procedure:
1.0 g (1.72 mmol) (E)-2-hydroxy-5-[4-(2-methoxycarbonylvinyl)benzoyloxy]benzoic acid 11-(2-methylacryloyloxy)undecyl ester, 0.37 g (2.24 mmol) 4-propylbenzoic acid and 58 mg (0.47 mmol) 4-dimethylaminopyridine were dissolved in 20 ml of dichloromethane. A suspension of 0.43g (2.24 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 10 ml dichloromethane were added dropwise in the course of 45 minutes. After 65 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 120 g silica gel using cyclohexane:ethyl acetate 4:1 and subsequent crystallisation form 50 ml isopropyl alcohol yielded 0.99 g (79%) (E)-5-[4-(2-methoxycarbonylvinyl)benzoyloxy]-2-(4-propylbenzoyloxy)benzoic acid 11-(2-methylacryloyloxy)undecyl ester as white powder, m.p. (C/N) 86.8° C., cl.p (N/I) 102.8° C.