Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:13]1[C:17](=O)[C@H:16]([OH:19])[C@@H:15]([OH:20])[C:14]1=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.B.[Na].Cl>COCCOC.O.CO>[CH2:6]([N:13]1[CH2:17][C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1[C@H](O)[C@@H](O)C(=O)N1Cc1ccccc1
Agent: B
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: O[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Temperature: 75 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
A solution of 32.2 ml (0.6 mole) sulfuric acid in 100 ml DME was added dropwise to a suspension of 66.4 g (0.3 mole) (3R,4R)-1-benzyl-3,4-dihydroxy-2,5-pyrrolidine dione (IIb) and 45.6 g (1.2 moles) sodium boron hydride in 400 ml 1,2-dimethoxyethane (DME) within 2.5 h at room temperature. The mixture was then agitated 4 h at 75° C. After it cooled off, 75 ml MeOH were added and the mixture rotated in to dryness. The residue was taken up in 300 ml water and compounded with 50 ml conc. hydrochloric acid. The mixture was then made alkaline and extracted with 200 ml toluene twice at 65° C. The extraction residue was taken up in 100 ml each of water and toluene, adjusted to be strongly acidic with hydrochloric acid and agitated overnight at room temperature. It was then made alkaline with 30% sodium hydroxide solution. After the addition of 200 ml toluene the organic phase was separated at 65° C. The aqueous phase was extracted again with 200 ml methylene chloride. After the organic phases were rotated in, 85 g oil remained. The latter was taken up in 400 ml ethyl acetate and washed twice with 80 ml water at 65° C. The ethyl-acetate phase was rotated in after drying over sodium sulfate. 60 g residue remained which was recrystallized from 150 ml ethyl acetate. 30.2 g (52.1%) (3S,4S)-1-benzyl-3,4-dihydroxypyrrolidine (IIIb) were obtained in two fractions.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:3]=1.[CH2:20]([Mg]Cl)[CH3:21]>C1COCC1>[CH3:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:20][CH3:21])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:11]=2)[N:3]=1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1C=O
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCC(O)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C

Procedure:
0.600 g (2.26 mmol) of the above prepared 2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine-3-carbaldehyde was dissolved in 11 ml of abs. THF and treated at −15° C. with 1.08 ml of 2.5 M ethyl magnesium chloride solution (in THF). After 30 Min., the reaction mixture was carefully poured onto crashed ice/NH4Cl, extracted twice with AcOEt, washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) produced finally 0.473 g of pure title compound as white crystals of mp. 97-99° C.
Reaction SMILES: [CH2:1]1[CH2:22][O:21][C:3]2([C:12]3[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][C:11]=3[O:13][CH3:14])[CH2:6][CH:5]([C:17]([O:19][CH3:20])=[O:18])[CH2:4]2)[O:2]1.C([O:25]P(OCC)OCC)C.O=O>O1CCCC1.CCOCC>[CH2:22]1[CH2:1][O:2][C:3]2([C:12]3[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][C:11]=3[O:13][CH3:14])[CH2:6][CH:5]([C:17]([O:19][CH3:20])=[O:18])[CH2:4]2)[O:21]1.[CH2:22]1[CH2:1][O:2][C:3]2([C:12]3[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][C:11]=3[O:13][CH3:14])[CH2:6][C:5]([OH:25])([C:17]([O:19][CH3:20])=[O:18])[CH2:4]2)[O:21]1
Reactant: CCOP(OCC)OCC
Agent: COC(=O)C1Cc2c(OC)ccc(OC)c2C2(C1)OCCO2
Agent: O=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1(O)Cc2c(OC)ccc(OC)c2C2(C1)OCCO2
Reaction time: 0.33 h
Yield: 66 %

Procedure:
(ii)(b) A solution of the lithium enolate of methyl rac-4,4-ethylenedioxy-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene-2-carboxylate was prepared in tetrahydrofuran as described in part (ii)(a) of this Example from 9.84 g of methyl rac-4,4-ethylenedioxy-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene-2-carboxylate. The enolate was added over a period of 5 minutes at -78° C. to a stirred solution of 11.2 ml of dry triethylphosphite in 60 ml of tetrahydrofuran through which a rapid stream of oxygen was passing. The passage of oxygen was maintained for 50 minutes and the temperature was held at -78° C. The reaction was then quenched by the addition of 8.8 ml of acetic acid. The cooling bath was removed and, after 5 minutes, 200 ml of water were added. After a further 20 minutes, most of the tetrahydrofuran was evaporated and the product was extracted into four 100 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with 200 ml of 10% aqueous potassium hydrogen carbonate, dried over magnesium sulphate, filtered and evaporated to give a yellow oil which was dissolved in 130 ml of ether and left to crystallise. There were obtained 6.86 g (66%) of methyl rac-4,4-ethylenedioxy-1,2,3,4-tetrahydro-2-hydroxy-5,8-dimethoxynaphthalene-2-carboxylate in the form of colourless crystals of melting point 74°-75° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:7][N:6]=1)=O.Cl.[CH3:19][O:20][NH2:21]>C(O)C>[CH3:19][O:20][N:21]=[C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:7][N:6]=1)[CH2:2][Br:1]
Reactant: O=C(CBr)c1ncc(OCC(F)(F)F)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CON=C(CBr)c1ncc(OCC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 84.9 %

Procedure:
To 1.3 g of 2-bromo-1-[3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethanone in 10 ml of ethanol, 362 mg of methoxyamine hydrochloride was added, and the mixture was stirred at room temperature for 13 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 0:100 to 5:95) to obtain 1.2 g of the desired product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3/[CH:13]=[C:14]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[C:15]([CH3:18])([CH3:17])[O:16]/3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:16][C:15]([CH3:17])([CH3:18])[C:14]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([N:32]5[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]5)=[O:25])=[CH:21][CH:20]=4)=[CH:13]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C(=O)O)cc1
Reactant: OC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C(=O)N2CCC(O)CC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid (50 mg, 0.137 mmol), 4-hydroxypiperidine (15 mg, 0.15 mmol), O-benzotriazol-1-yl-N,N,N,N′-tetramethyluronium hexafluorophosphate (HBTU) (57 mg, 0.15 mmol) and diisopropylethylamine (39 mg, 0.30 mmol) in 3 mL of anhydrous DMF was stirred at room temperature. The mixture was poured into 75 mL of water. The precipitates were filtered, washed with water, and dried in vacuo to give (3E)-6-fluoro-3-[4-{4-[(4-hydroxypiperidin-1-yl)carbonyl]phenyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as orange solid. Yield: 52 mg, 85%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[CH:18]1([CH3:30])[CH2:23][CH2:22][CH:21]([CH:24]([CH3:26])[CH3:25])[CH:20]([C:27](Cl)=[O:28])[CH2:19]1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH:6][C:27]([CH:20]1[CH2:19][CH:18]([CH3:30])[CH2:23][CH2:22][CH:21]1[CH:24]([CH3:26])[CH3:25])=[O:28]
Reactant: NCCc1ccccc1Br
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCC(C(C)C)C(C(=O)NCCc2ccccc2Br)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A 100 mL round bottom flask equipped with a stir bar was charged with CH2Cl2 (30 mL), 2-bromo-phenethylamine (1.0 g, 5.00 mmol) and triethylamine (684 μl, 5.05 mmol). The reaction solution was treated with menthoyl chloride (1.02 g, 5.05 mmol) in one portion and stirred at ambient temperature for 30 minutes. The reaction was diluted with CH2Cl2 (50 mL) and washed with water (3×100 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a thick oil (1.8 g). Product was used for next step without purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10]O)[CH3:2].N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:36]I>CC#N.CCOCC>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][I:36])[CH3:2]
Reactant: II
Reactant: CCc1ccccc1CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: CCc1ccccc1CCI
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.5 %

Procedure:
Into a 50-mL round-bottom flask was placed ether (10 mL), CH3CN (5 mL) and 2-(2-ethylphenyl)ethan-1-ol (900 mg, 5.99 mmol, 1.00 equiv). Then imidazole (570 mg, 8.38 mmol, 1.40 equiv), PPh3 (2.20 g, 8.39 mmol, 1.40 equiv) and I2 (1.98 g, 7.80 mmol, 1.30 equiv) were added at 0° C. The resulting solution was stirred for 6 h at room temperature. The reaction was then quenched by the addition of 10 mL of saturated Na2SO3 solution. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined, dried over Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). Purification afforded 1.16 g (74%) of 1-ethyl-2-(2-iodoethyl)benzene as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([C:23]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([N:30](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:24]=3)[C:10]([NH:13][C:14]3[CH:15]=[N:16][C:17]([O:21][CH3:22])=[C:18]([F:20])[CH:19]=3)=[N:11][CH:12]=2)[CH2:3][CH2:2]1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[O:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[C:9]([C:23]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=3)[C:10]([NH:13][C:14]3[CH:15]=[N:16][C:17]([O:21][CH3:22])=[C:18]([F:20])[CH:19]=3)=[N:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4=CCOCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C3=CCOCC3)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 80 °C
Yield: 79.5 %

Procedure:
A solution of 4-(5-(3,6-dihydro-2H-pyran-4-yl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (140 mg, 0.215 mmol) in 3 mL of TFA was treated with 0.15 mL of trifluoromethanesulfonic acid and heated at 80° C. in an oil bath for 3 h. It was concentrated and the dark residue was stirred in 15 mL of EtOAc then treated with 5 mL of 1 N NaOH. The aqueous layer was extracted with 2×10 mL of DCM. The combined EtOAc extracts and DCM extracts were concentrated. The residue was purified on a silica gel column and eluted with 35-100% EtOAc in DCM to give 4-(5-(3,6-dihydro-2H-pyran-4-yl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (70 mg, 79% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (s, 1H), 8.85 (d, J=2.6 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.41-8.35 (m, 2H), 7.91 (br., 1H), 7.76 (br., 1H), 6.24 (m, 1H), 4.24 (m, 2H), 3.94 (s, 3H), 3.84 (m, 2H), 2.45 (s, 5H). m/z (ESI, positive ion) 410.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[NH:8][C:7]=12>C(O)C>[N:13]1([C:11]([C:9]2[NH:8][C:7]3=[CH:2][N:3]=[CH:4][CH:5]=[C:6]3[CH:10]=2)=[O:12])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(c1cc2ccnc(Cl)c2[nH]1)N1CCCC1
Solvent: CCO
Product: O=C(c1cc2ccncc2[nH]1)N1CCCC1
Yield: 46 %

Procedure:
2-(1-Pyrrolidinylcarbonyl)-1H-pyrrolo[2,3-c]pyridine (22 mg, 46%) was prepared as an off-white solid following the procedure described for Example 27 using 7-chloro-2-(1-pyrrolidinylcarbonyl)-1H-pyrrolo[2,3-c]pyridine (Example 13) and ethanol as a solvent: mp 260-275° C. dec.; 1H NMR (300 MHz, CD3OD) δ1.98-2.10 (4H, m), 3.66-3.71 (2H, m), 3.89-3.94 (2H, m), 7.10 (1H, s), 7.74 (1H, d, J=5.4 Hz), 8.13 (1H, d, J=5.7 Hz), 8.82 (1H, s); ESI MS m/z 216 [C12H13N3O+H]+; HPLC (Method A) 93.3% (AUC), tR=10.3 min.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].O>CO>[F:16][C:12]1[N:11]=[C:10]([N:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)N1CCN(c2cccc(F)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Fc1cccc(N2CCNCC2)n1
Yield: 103 %

Procedure:
A solution of 1-acetyl-4-(6-fluoropyridin-2-yl)piperazine (5.5 g) and sodium hydroxide (3.0 g) in methanol (30 ml)—water (30 ml) was refluxed under heating for 5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The solvent was evaporated to give the title compound (4.6 g) as a pale-yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3cccc(OCc4ccccc4)c3)nc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2cnc(-c3cccc(O)c3)nc2)cc1

Procedure:
8.00 g (23.40 mmol) of 5-bromo-2-(3-benzyloxyphenyl)pyrimidine, 7.03 g (28.10 mmol) of 4-octyloxybenzeneboronic acid (preparation analogous to 3-benzyloxybenzeneboronic acid), 7.00 g (65.52 mmol) of sodiumcarbonate and 0.27 g (0.23 mmol) of tetrakis(triphenylphosphine)palladium(0) are heated at 80° C. for 2 hours in 200 ml of toluene, 100 ml of ethanol and 50 ml of water. The reaction mixture is subsequently partitioned between water and ether, the organic phase is washed twice with sodium chloride solution, dried over sodium sulfate and evaporated, and the residue is purified by chromatography (silica gel/dichloromethane: ethyl acetate=98:2), giving 10.66 g of 2-(3-benzyloxyphenyl)-5-(4-octyloxyphenyl)pyrimidine. ##STR15## 10.66 g (22.84 mmol) of 2-(3-benzyloxyphenyl)-5-(4-octyloxyphenyl)pyrimidine are hydrogenated together with 2.00 g of Pd (10%)/C in 100 ml of tetrahydrofuran until the calculated volume of hydrogen has been consumed, the catalyst is subsequently filtered off, and the filtrate is evaporated and dried, giving 8.43 g of 2-(3-hydroxyphenyl)-5-(4-octyloxyphenyl)pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[CH2:11]([N:13]([CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=1)([OH:20])[C:16]([F:18])([F:19])[F:17])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH3:12]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1C

Procedure:
Prepared similarly to Example 1 from 2-methylbenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:28]=[C:24]([C:25]([NH2:27])=[O:26])[C:23]([OH:29])=[CH:22][CH:21]=1.O>CS(C)=O>[C:25]([C:24]1[CH:28]=[C:20]([CH:21]=[CH:22][C:23]=1[OH:29])[O:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8])(=[O:26])[NH2:27]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: NCCCCOc1ccc(O)c(C(N)=O)c1
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccccc1OCC(O)CNCCCCOc1ccc(O)c(C(N)=O)c1
Reaction time: 1 h

Procedure:
7.3 g of 2-(2,3-epoxypropoxy)benzonitrile are added to a solution of 6.7 g of 5-(4-aminobutoxy)salicylamide in 60 ml of dimethyl sulphoxide and the mixture is stirred for 1 hour in a bath at 90°. The reaction mixture is poured into 300 ml of water and extracted twice with 200 ml of ethyl acetate each time. Working up analogously to Example 23 yields crude 1-[4-(3-carbamoyl-4-hydroxyphenoxy)butylamino]-3-(2-cyanophenoxy)propan-2-ol as a viscous oil, the IR- and 1H-NMR-spectra of which are in concordance with the assumed structure and the Rf-value of which is 0,51 according to thin-layer-chromatography on silicagel using a mixture of ethylacetate-ethanol-conc. ammonia 24:12:4 as the eluent.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:18][C:19]1[C:36]([CH3:37])=[CH:35][C:22]2[NH:23][C:24]([C:26]3[NH:27][N:28]=[C:29]4[C:34]=3[CH2:33][CH2:32][NH:31][CH2:30]4)=[N:25][C:21]=2[CH:20]=1.O>CN(C)C=O>[CH3:37][C:36]1[C:19]([CH3:18])=[CH:20][C:21]2[NH:25][C:24]([C:26]3[NH:27][N:28]=[C:29]4[C:34]=3[CH2:33][CH2:32][N:31]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)[CH2:30]4)=[N:23][C:22]=2[CH:35]=1
Reactant: Cc1cc2nc(-c3[nH]nc4c3CCNC4)[nH]c2cc1C
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2nc(-c3[nH]nc4c3CCN(c3ccc([N+](=O)[O-])cn3)C4)[nH]c2cc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.5 %

Procedure:
287 mg of 2-chloro-5-nitropyridine and 500 mg of potassium carbonate are added to a solution of 500 mg of 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine hydrochloride in 5 ml of dimethylformamide. After stirring for 20 hours at ambient temperature, the reaction medium is added to 50 ml of water. The precipitate formed is recovered by filtration through sintered glass, washed with 3 times 15 ml of water and then dried under reduced pressure. 548 mg of 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-6-(5-nitropyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo-[3,4-c]pyridine are thus obtained in the form of a yellow powder, the characteristics of which are as follows:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][CH:8]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:27])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:9]([OH:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].O=[Cr](=O)(O[Cr](=O)([O-])=O)[O-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:7][CH:8]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:27])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:25])[CH3:26])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(O)C(C)CCC=C(C)CCC=C(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CC(=O)C(C)CCC=C(C)CCC=C(C)C
Temperature: 0 °C
Yield: 57.2 %

Procedure:
To a mixture of pyridine (132 ml) and ethyl 3,7,11-trimethyl-6,10-dodecadien-2-ol-1-carboxylate (132 g), the Cornforth reagent (prepared by adding dropwise a solution of chromium trioxide (223 g) in water (150 ml) to pyridine (2230 ml) while cooling with ice water) is added, and the resultant mixture is allowed to stand at room temperature. After removal of the precipitate by filtration, the reaction mixture is admixed with water and extracted with ether. The ether extract is washed with water, dried and evaporated. The residual material is distilled under reduced pressure to give ethyl 3,7,11-trimethyl-6,10-dodecadien-2-one-1-carboxylate (75 g) as a pale yellow oil. B.P. 125° to 129°C/0.06 mmHg. IR: 1740, 1225 cm-1 (COO); 1710 cm-1 (C=O). NMR (carbon tetrachloride): δ 1.25 (m), 1.61 (s), 1.69 (s), 1.98 (s), 2.0-2.8 (m), 3.33 (s), 4.15 (m), 4.8-5.25 (m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]3[C:3]=2[C:21]2[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2ccn3c(=O)n(CC(C)C)nc3c2-c2ccc(C)cc2)cc1
Temperature: 200 °C
Yield: 20.8 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.13 mmol), 4-methylphenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (40 mg, 0.25 mmol) in water (0.3 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 7 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (10 mg, 0.027 mmol) as a pale yellow solid. MS: [M+H]+=372.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.[Na].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][CH2:20][CH2:19][CH:18]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:17]=2[CH:39]=1>C(COC)OC>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:22][CH2:21][CH2:20][CH2:19][CH:18]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:17]=2[CH:39]=1
Reactant: CCOC(=O)CC1CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)cc21
Agent: [Na]
Solvent: c1ccc2ccccc2c1
Solvent: COCCOC
Product: CCOC(=O)CC1CCCNc2ccc(Cl)cc21
Reaction time: 1 h
Yield: 36.8 %

Procedure:
To a solution of naphthalene (15.5 g) in dimethoxyethane (100 ml) was added sodium metal (2.79 g) in portions at 0° C. and the solution was stirred at the same temperature for 1 hour. The naphthilide was added to a solution of 7-chloro -5-ethoxycarbonylmethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine (9.89 g) in dimethoxyethane (400 ml) at -60° C. and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was quenched with water and the solution was extracted with chloroform. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give an oil and the crude oil was purified by silica gel column to give 7-chloro-5-ethoxycarbonylmethyl -2,3,4,5-tetrahydro-1H-1-benzazepine (2.31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.[CH3:19][C:20](Cl)=[O:21].Cl>ClCl.CN(C1C=CC=CN=1)C>[C:20]([O:12][CH2:11][CH:10]=[CH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:21])[CH3:19]
Reactant: CC(=O)Cl
Reactant: OCC=Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccccn1
Agent: Cl
Agent: ClCl
Solvent: c1ccncc1
Product: CC(=O)OCC=Cc1ccc(Cl)c(Cl)c1
Temperature: 23 °C
Yield: 96.8 %

Procedure:
Treat a solution of the product of step 2 (13.2 g, 65 mmol) in CH2 Cl2 (250 mL) at 0° C. with pyridine (7.89 mL, 97.5 mmol, 1.5 eq) and dimethylaminopyridine (397 mg, 3.25 0.05 eq), followed by CH3COCl (6.48 mL, 74.75 mmol, 1.15 eq). Allow the mixture to warm to 23° C., pour into 1M HCl (100 mL) and wash the resulting organic layer again with 1M HCl (100 mL), followed by water (5×100 mL; pH=6.5-7). Dry the organic layer (Na2SO4) and concentrate to obtain 15.4 g (62.9 mmol, 97%) of 3-(3,4-dichlorophenyl)-2-propene-1-ol acetate as a colorless oil.