Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1([CH2:23][CH2:24]I)[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[C:31]([OH:34])(=[S:33])[CH3:32]>CC(C)=O>[C:31]([S:33][CH2:24][CH2:23][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:9]1=[O:22])(=[O:34])[CH3:32]
Reactant: CC(O)=S
Reactant: COC(=O)C1C=CCN2C(=O)C(CCI)(Cc3ccccc3)C(=O)N12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1C=CCN2C(=O)C(CCSC(C)=O)(Cc3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
(b) A mixture of 0.5 g of methyl 2-benzyl-2,3,5,8-tetrahydro-2-(2-iodoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, 0.15 g of potassium acetate and 0.1 g of thioacetic acid in 40 ml of acetone was stirred at room temperature for 5 hours. The solvent was removed by evaporation and the residue was partitioned between dichloromethane and water. The organic phase was separated, dried over magnesium sulfate and evaporated to give 0.4 g (90%) of methyl 2-(2-acetylthioethyl)-2-benzyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (diastereomer A) in the form of a pale yellow oil.
Reaction SMILES: O[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].N1C=CC=CC=1.S(Cl)([Cl:22])=O>C(Cl)Cl.[Cl-].[Na+].O.C1(C)C=CC=CC=1>[Cl:22][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(CCO)c1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(CCCl)c1ccc(O)cc1

Procedure:
A solution of 6.81 g crude 4-(2-hydroxy-ethansulfonyl)-phenol in 35 ml CH2Cl2 was treated at room temperature with 5.3 ml (65.9 mmol) pyridine. To the reaction mixture was added at 0° C. dropwise over 15 min a solution of 4.2 ml (57.1 mmol) thionyl chloride in 10 ml CH2Cl2. After 65 h at room temperature the reaction mixture was treated with 35 ml brine, extracted and the organic phases were washed twice with total 100 ml aqueous half saturated NaCl solution. The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure to yield 6.77 g crude product. The crude product was dissolved in 2.5 ml CH2Cl2 and 25 ml toluene, stirred 24 h at 50° C., 24 h at room temperature and 48 h at 0° C. The so formed suspension was filtered to yield 5.44 g (86.5% over 2 steps) product as white crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6][CH2:7][CH3:8])=O.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([OH:23])=[C:18](C(=O)C)[CH:19]=1.S(=O)(=O)(O)O>C(O)C>[CH2:11]([O:10][C:3]([C:4]1[O:6][C:7]2[C:18]([C:17](=[O:23])[CH:16]=1)=[CH:19][C:14]([Cl:13])=[CH:15][CH:8]=2)=[O:9])[CH3:12]
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: CCOC(=O)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In an argon atmosphere, ca. 60% oily sodium hydride (1.68 g) was added to ethanol (10 mL). The mixture was stirred at room temperature for 10 minutes. Diethyl oxalate (3.36 mL) was added thereto, 5′-chloro-2′-hydroxyacetophenone (2.82 g) dissolved in ethanol (20 mL) was added dropwise to the resultant mixture, and ethanol (40 mL) was further added, followed by refluxing for 1.5 hours and stirring at 50° C. for 14 hours. To the reaction mixture, concentrated sulfuric acid (1.5 mL) and ethanol (10 mL) were added, and the mixture was refluxed for 4 hours. The resultant mixteure was cooled, concentrated under reduced pressure to reduce the solvent by half, and toluene and 1N aqueous sodium hydroxide (15 mL) were added to the concentrated mixture. The resultant mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1). The resultant solid was washed with hexane, to thereby give the title compound (1.20 g).
Reaction SMILES: C([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:36])[CH2:5][CH2:6][CH2:7][N:8]=[N+:9]=[N-:10])(=O)C.O>O1CCOCC1.Cl>[N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:36])=[N+:9]=[N-:10]
Reactant: CCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(CCCN=[N+]=[N-])C(C)=O)c(F)c3)cc(=O)c12
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCCCCNc1c(F)cc(F)c2oc(-c3ccc(NCCCN=[N+]=[N-])c(F)c3)cc(=O)c12
Yield: 56.6 %

Procedure:
51 mg (0.10 mmol) of the resulting 2-[4-[N-acetyl-N-(3-azidopropyl)amino]-3-fluorophenyl]-6,8-difluoro-5-pentylamino-4H-1-benzopyran-4-one was dissolved in a mixed solvent of 1.5 ml of dioxane and 1.5 ml of concentrated hydrochloric acid and the mixture was heated at reflux for 3 hours. The reaction solution was cooled, water was added, the solution was made weak alkaline and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform) to give 26 mg (56%) of 2-[4-(3-azidopropylamino)-3-fluorophenyl]-6,8-difluoro-5-pentylamino-4H-1-benzopyran-4-one.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:34])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[CH:32]=[O:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.P([O-])(O)(O)=[O:41].[Na+].Cl([O-])=O.[Na+].Cl>O.C(O)(C)(C)C>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:34])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:32]([OH:41])=[O:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C=O)c1Cl)(c1ccccc1)c1ccccc1
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C(=O)O)c1Cl)(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 71.9 %

Procedure:
1-(3-tert-Butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-formylpyrrole (1.51 g) was dissolved in a mixture of water (8 ml) and tert-butyl alcohol (30 ml), and 2-methyl-2-butene (923 mg) and sodium dihydrogen phosphate (392 mg) were added to the mixture in water bath. To the mixture was added portionwise sodium chlorite (1.19 g), and the mixture was stirred for 1 day at the same temperature. The reaction mixture was cooled in an ice bath, adjusted to pH 4 with 1M hydrochloric acid and extracted with chloroform. The organic layer was separated, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with chloroform-n-hexane-methanol to give 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-carboxypyrrole (1.12 g) as an oil.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: O=C1CCC(c2cccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 140 °C
Reaction time: 48 h

Procedure:
4-(2-Fluoropyridin-3-yl)cyclohexanone (0.05 g, 0.26 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.19 g, 0.78 mmol), and cesium carbonate (0.25 g, 0.78 mmol) were mixed in NMP (1 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 140° C. for 48 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were washed with 1 M aqueous sodium hydroxide, washed with sat. sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was partially purified by silica gel chromatography. The impure product was then dissolved in a minimal amount of DCM, and hexanes were added until a precipitate formed. The resulting suspension was partially concentrated and filtered to give 4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)cyclohexanone. MS (ESI, pos. ion) m/z: 412.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5].CS(C)=O.[OH-].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30]>Cl.C(OC)(C)(C)C>[OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5]
Reactant: O=C(c1ccccc1O)c1ccccc1O
Reactant: CCOC(=O)CCCCCBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: O=C(O)CCCCCOc1ccccc1C(=O)c1ccccc1O
Temperature: 45 °C
Reaction time: 20 h
Yield: 26.5 %

Procedure:
A 250 mL round bottom flask equipped with a magnetic stirrer bar and a reflux condenser was charged with 10.32 g (48.2 mmol) of 2,2′-dihydroxybenzophenone and 100 mL of dimethylsulfoxide (DMSO). Potassium hydroxide (2.91 g, 51.9 mmol) that had been ground to a powder was added to the clear solution. The reaction mixture was heated to 45° C., until most of the solid had dissolved. The resulting red slurry was treated with 8.80 mL (11.04 g, 49.5 mmol) of ethyl 6-bromohexanoate. After stirring for 20 hr at 25° C., the clear reaction mixture was diluted with aqueous 1% hydrochloric acid and methyl t-butyl ether (MTBE). The layers were separated. The organic phase was washed with water (2×50 mL) and brine (1×40 mL), dried over sodium sulfate and concentrated. The residue was taken up in 100 mL of tetrahydrofuran (THF) and treated with potassium trimethylsilanoate (15.09 g, 118 mmol). The orange solution was stirred for 20 hr at 25° C., diluted with aqueous 4% hydrochloric acid to pH 7.5 and washed with MTBE. The organic phase was extracted with aqueous 3% sodium bicarbonate solution. The combined aqueous phases were acidified to pH 2 with aqueous 4% hydrochloric acid and extracted with 60 mL of MTBE. This organic phase was washed with brine (1×40 mL), dried over sodium sulfate and concentrated. The residue was purified by flash chromatography using 80% hexanes/ethyl acetate (spiked with 0.5% acetic acid). The product (4.2 g, 27%) was isolated as an off-white solid, mp 89-91° C. Combustion analysis: Found: C, 69.50; H, 6.04%; C19H20O5 requires C, 69.50; H, 6.14% 1H NMR (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 11.5, bs, 1H (OH); δ 7.5, t, 2H, (aryl H's); δ 7.4, dd, 1H (aryl H); δ 7.3, dd, 1H (aryl H); δ 7.15, d, 1H (aryl H); δ 7.1, t, 1H (aryl H); δ 7.0, d, 1H (aryl H); δ 6.9, t, 1H (aryl H); δ 3.9, t, 2H, (CH2 α to O); δ 2.05, t, 2H(CH2 α to COOH); δ 1.4, m, 4H (other two CH2's); δ 1.0, p, 2H(CH2 in middle of chain).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:11](Br)[CH:12]=[CH2:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH:8][CH2:13][CH:12]=[CH2:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCBr
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN[C@H](C)C(=O)OC(C)(C)C

Procedure:
D-Alanine t-butylester (68) is treated with one equivalent allyl bromide and one equivalent of triethylamine in toluene under reflux. The solvent is evaporated and the product is purified by flash chromatography on silica gel to give (69).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[NH2:9][CH2:10][C:11]#[N:12]>>[C:1]([NH:12][CH2:11][C:10]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: N#CCN
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Product: CC(C)(C)C(=O)NCC#N

Procedure:
The compound was prepared according to Example 1 a) from 36.17 g pivaloylchloride and 27.76 g aminoacetonitrile hydrochloride
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:3].[C:26](Cl)(=[O:28])[CH3:27].Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:26]([O:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH3:3])(=[O:28])[CH3:27]
Reactant: CC(O)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Reaction time: 2 h
Yield: 97.9 %

Procedure:
29.9 g (0.09 mol) of III-15 was dissolved in a mixed solution of 150 ml of toluene and 50 ml of pyridine, followed by addition of 9.42 g (0.12 mol) of acetyl chloride at 15°-20° C. over a period of 2 hours. The mixture was maintained at the same temperature for 2 hours and then at 40°-45° C. for another 2 hours. The reaction mixture was cooled below 10° C. and added with 300 ml of 3N hydrochloric acid. After separating the liquid phase, the organic layer was washed with water, 5% sodium hydrogencarbonate and water successively in that order and concentrated under reduced pressure. The residue was purified by column chromatography to give 33.0 g (98% yield) of benzyl 4'-(1-acetoxyethyl)-4-biphenylcarboxylate (IV-15).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.C[O-].[Na+].Cl.C[CH2:24][O:25]C(C)=O>CN(C=O)C>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[O:9][C:10]3[C:2]([O:25][CH3:24])=[CH:3][C:4]([OH:18])=[CH:5][C:6]=3[CH:7]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc(-c2cc3cc(O)cc(Br)c3o2)cc1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 160 °C

Procedure:
A solution consisting of 58 (1.5 g, 4.9 mmol) in DMF (25 mL) was treated with CulBr (1.0 g, 6.5 mmol) and NaOMe (6 mL, 4.4 N in MeOH, 27 mmol) and heated to 160° C. for approximately 1 hour. The reaction mixture was allowed to cool and then worked up by adding 2 N HCl and EtOAc. The EtOAc layer was washed with NaHCO3 aq, brine and dried over MgSO4. The solution was concentrated and chromatographed on silica gel (1:4 EtOAc/hexanes to 3:7 EtOAc/hexanes) to yield 0.47 g of pdt: p=167-168° C., 1H NMR (DMSO-d6) δ 9.84 (br s, 1 H), 9.18 (br s, 1 H), 7.67 (d, 2 H, J=8.6 Hz), 6.99 (s, 1H), 6.86 (d, 2 H, J=8.7 Hz), 6.46 (d, 1 H, J=2.1 Hz), 6.34 (d, 1 H, J=2.1 Hz), 3.89 (s, 3 H); MS 257 (M+H)+.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.CON(C)[C:16]([C@@H:18]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:17].[Cl-].[Na+]>C1(C)C=CC=CC=1>[CH:16]([C@@H:18]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:17]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Agent: COCCO[Al+]OCCOC
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCC[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 54.0 mL (180.0 mmol) of 65 wt % bis (2-methoxyethoxy) aluminum hydride in toluene in 100 mL of toluene at −20° C. was added a solution of 35.0 g (120.0 mmol) of tert-butyl (1S)-1-{[methoxy(methyl)amino]carbonyl}pentylcarbamate in 100 mL of toluene over 30 min. After stirring at −20° C. for 2 h, 300 mL of 3M aqueous sodium chloride was added dropwise, and the layers were separated. The toluene portion was washed with 100 mL of 1 N hydrochloric acid (2×), 50 mL of 0.1 N sodium hydroxide (2×), 50 mL of brine, dried over anhydrous magnesium sulfate, and then concentrated to 200 mL. The aldehyde solution was used immediately. An aliquot was removed and concentrated, and the aldehyde was analyzed immediately. 1H-NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 7.23 (d, J=7 Hz, 1H), 3.75 (m, 1H), 1.70–1.08 (m, 6H), 1.36 (s, 9H), 0.81 (t, J=6 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:20])[CH:18]=[CH2:19].CC(C)([O-])C.[K+]>O1CCCC1>[CH2:22]([O:21][C:17](=[O:20])[CH2:18][CH2:19][O:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: C=CC(=O)OCCCCCCCCCCCCCCCCCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCON(Cc1ccccc1)Cc1ccccc1

Procedure:
The procedure of Example I is repeated using 10.66 g of N,N-dibenzylhydroxylamine, 16.03 g of n-octadecyl acrylate, and 0.50 g of potassium-tert-butoxide in 100 ml of tetrahydrofuran, to afford the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]2[O:8][CH2:9][O:10][C:5]2=[CH:4][C:3]=1[CH:11]([C:13]1[C:14]([Cl:23])=[N:15][CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])[OH:12]>[O-2].[O-2].[Mn+4]>[CH2:9]1[O:10][C:5]2[C:6](=[CH:7][C:2]([CH3:1])=[C:3]([CH:4]=2)[C:11]([C:13]2[C:14]([Cl:23])=[N:15][CH:16]=[CH:17][C:18]=2[C:19]([F:21])([F:22])[F:20])=[O:12])[O:8]1
Reactant: Cc1cc2c(cc1C(O)c1c(C(F)(F)F)ccnc1Cl)OCO2
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1cc2c(cc1C(=O)c1c(C(F)(F)F)ccnc1Cl)OCO2
Yield: 20.3 %

Procedure:
Using 1.5 g (4.3 mmol) of (2-methyl-4,5-(methylenedioxy)phenyl)(2-chloro-4-trifluoromethyl-3-pyridyl)methanol obtained in step (c) and 8.0 g (92 mmol) of manganese dioxide, 0.3 g (yield 22%) of 3-[4,5-(methylenedioxy)-2-methylbenzoyl]-2-chloro-4-trifluoromethylpyridine (compound No. 13; m.p. 119-122° C.) was obtained by a process in accordance with step (b) of Synthesis Example 1.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][N:17]([C:23]4[C:28]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: CC(C)S(=O)(=O)c1cccnc1Cl
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)c1cccnc1N1CCc2c(ncnc2Nc2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound was prepared according to the procedure given for Example 9 using N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.073 g, 0.25 mmol), 2-chloro-3-(isopropylsulfonyl)pyridine (0.070 g, 0.32 mmol) and N,N-diisopropylethylamine (0.082 mL, 0.47 mmol) to obtain 0.073 g of a white solid.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:13]([O:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14]>C(O)CCCC>[C:13]([O:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:2]3[NH:6][C:5]4[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=4[N:3]=3)[CH2:28][CH2:27]2)=[CH:21][CH:20]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Reactant: COc1ccc2nc(Cl)[nH]c2c1
Solvent: CCCCCO
Product: COc1ccc2[nH]c(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)nc2c1
Temperature: 120 °C
Yield: 82.1 %

Procedure:
2-Chloro-5-methoxybenzimidazole (0.089 g, 0.49 mmol) was added to a solution of (49) (0.14 g, 0.5 mmol) in n-pentanol (3 mL) at 25° C. The mixture was heated to 120° C. and was maintained at that temperature for 12 h. The reaction mixture was cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.17 g (83.3%) of the title compound: TLC (Rf =0.30; 5% MeOH/CH2Cl2); 1H NMR (DMSO) δ 13.40 (br s, 1H), 7.63 (d, 2H, J=8.3), 7.29 (d, 1H, J=8.7), 6.91 (s, 1H), 6.83 (d, 1H, J=8.4), 6.65 (d, 2H, J=8.3), 6.50 (s, 1H), 4.13 (d, 2H, J=12.7), 3.77 (s, 3H), 3.73 (m, 1H), 3.47 (m, 4H), 2.06 (d, 2H, J=11.0), 1.48 (s, 9H); 13C NMR (DMSO) δ 165.2, 156.1, 151.3, 149.8, 131.0, 130.9, 124.0, 117.8, 111.8, 111.3, 110.2, 96.4, 79.0, 55.7, 47.3, 45.6, 30.2, 30.0; HRMS (FAB) m/z 423.2388 (M+H)+ (C24H30N4O3 requires 423.2389); Anal. (C24H30N4O3 ·1HCl·1/2H2O) C, H, N.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c(OCc3ccccc3)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
4-hydroxy-2-methyl indole 1 (50 g, 0.339 mole) was dissolved in anhydrous DMF (1 L). To the mixture sodium hydride 60% in mineral oil (27.9 g, 0.697 mole) was added. The mixture was left to stir at rt. for 1 h. To the mixture benzyl bromide (82.7 mL, 0.697 mole) was added drop-wise. The mixture was left to stir at room temperature for 18 h. The reaction was diluted with ethyl acetate (4 L) and washed with water (5×500 mL) then brine (1 L). The organic layer was separated and dried with magnesium sulphate and concentrated. The orange oily residue was purified by column chromatography (6:1 Hexane:EtOAc) to afford 86 g (72%) of 2 as an yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19][CH3:18])[CH2:31][CH2:30]2)[N:3]=1
Reactant: CSc1ccccc1N1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-methylsulfanyl-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield the 2,4-bis-(2-hydroxy-ethylamino)-6-[4-(2-methylsulfanyl-phenyl)-piperazin-1-yl]-pyrimidine-5-carbonitrile as a yellowish lyophilisate; MS: [M+H]+=430.