Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([NH:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:7][CH2:6]2.[C:19]([S:22][CH2:23][CH:24]([CH2:28][S:29][C:30](=[O:32])[CH3:31])[C:25](Cl)=[O:26])(=[O:21])[CH3:20].O>CC(N(C)C)=O>[C:19]([S:22][CH2:23][CH:24]([CH2:28][S:29][C:30](=[O:32])[CH3:31])[C:25]([N:14]([CH:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[CH2:6][CH2:7]1)[CH2:15][C:16]([OH:18])=[O:17])=[O:26])(=[O:21])[CH3:20]
Reactant: COc1cc2c(cc1OC)C(NCC(=O)O)CC2
Reactant: CC(=O)SCC(CSC(C)=O)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2c(cc1OC)C(N(CC(=O)O)C(=O)C(CSC(C)=O)CSC(C)=O)CC2
Temperature: 25 °C
Yield: 45.5 %

Procedure:
N-(5,6-Dimethoxy-1-indanyl)glycine (4.0 g) is suspended in 40 ml of dimethylacetamide, then 4.4 g of 3-acetylthio-2-acetylthiomethylpropionyl chloride is added dropwise with stirring at room temperature, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into 400 ml of water and extracted with 300 ml of ethyl acetate. The extract is washed with 30 ml of 10% hydrochloric acid and with water, and dried. After ethyl acetate is distilled off under reduced pressure, ethyl ether is added to the residue and the mixture is allowed to stand at room temperature. The resulting crystalline precipitates are collected by filtration to give 3.4 g of N-(3-acetylthio-2-acetylthiomethylpropionyl)-N-(5,6-dimethoxy-1-indanyl)glycine as colorless needles melting at 140°-143° C.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH:10]([NH2:14])([CH2:12][CH3:13])[CH3:11]>>[CH3:11][CH:10]([NH:14][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:12][CH3:13]
Reactant: CCC(C)N
Reactant: CCOC(=O)C(F)(F)F
Product: CCC(C)NC(=O)C(F)(F)F

Procedure:
In a procedure similar to Example 6, ethyl trifluoroacetate (295 g, 2.07 m) was reacted with sec-butylamine. The resulting amide distilled at 72.5° C./8 mm Hg and amounted to 285 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]#[N:16])[N:3]=1.Br[CH2:18][CH2:19][O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH2:19][O:20][CH3:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]#[N:16])[N:3]=1
Reactant: N#Cc1nc(N)nc(Nc2ccccc2)n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCN(c1ccccc1)c1nc(N)nc(C#N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-amino-6-phenylamino-[1,3,5]triazine-2-carbonitrile (prepared in an analogous manner to Intermediate 5, 100 mg, 470 μmol), 1-bromo-2-methoxyethane (50 μl, 0.52 mmol) and potassium carbonate 130 mg, 0.94 mmol) in DMF (5 ml) was heated to 100 C and stirred 3 h. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated under vacuum to give the crude product which was used without further purification (400 mg, >100%, contains DMF). Method C HPLC-MS: MH+ requires m/z=271. Found: m/z=271, Rt=1.23 min (52%).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][S:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:11])[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:21][C:22]1[N:23]=[C:24]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([F:40])([F:39])([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[O:25][CH:26]=1.O>CN(C=O)C>[F:38][S:35]([F:36])([F:37])([F:39])([F:40])[C:32]1[CH:33]=[CH:34][C:29](/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][S:10]([CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[O:11])=[CH:18][CH:17]=3)[N:23]=2)=[CH:30][CH:31]=1
Reactant: O=S(CCn1ccnn1)Cc1ccc(O)cc1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(S(F)(F)(F)(F)F)cc3)n2)cc1
Reaction time: 0.25 h
Yield: 17.1 %

Procedure:
14 mg (0.50 mmol) 95% sodium hydride were given to a solution of 126 mg (0.50 mmol) 4-(2-[1,2,3]Triazol-1-yl-ethanesulfinylmethyl)-phenol in 3.0 ml DMF and stirred for 15 min. 173 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 6 ml water the resulting precipitate was washed with water (2×), water/methanol 1:1 (2×), ethyl acetate/n-heptane 3:1 (1×), little ethyl acetate (1×), diethyl ether (1×) and dried in vacuum at 40° C. Further purification by chromatography on silica gel (eluent:ethyl acetate/methanol 15:1) and stirring of the isolated product with little ether and ethyl acetate and drying gave 48 mg (17%) white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11](=[O:14])([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:14][C:11]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[N+:8]([O-:10])=[O:9])([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1Oc1ccccc1[N+](=O)[O-]
Yield: 41.7 %

Procedure:
A solution of 3-[[[3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenol (100 mg, 0.23 mmol), 1-bromo-2-nitrobenzene (52.4 mg, 0.26 mmol), copper(I) trifluoromethanesulfonate benzene complex (3 mg, 2.5 mol %) and cesium carbonate (100 mg, 0.31 mmol) in toluene (1 mL) and ethyl acetate (1 mL) was heated at 95° C. in a sealed vial for 4 d. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 14.1 mg (11%) of the desired 2-nitrophenyl ether product as an orange oil. HRMS calcd. for C24H20F7N2O5: 549.1260 [M+H]+, found: 549.1235. 1H NMR (CDCl3) δ 3.63 (dd, 1H), 3.84 (dd, 1H), 4.35-4.42 (m, 1H), 4.64 (s, 2H), 5.90 (tt, 1H), 6.47-6.67 (m, 3H), 6.98-7.50 (m, 8H), 7.97 (d, 1H)
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N:6]2[CH:12]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:2][C:3]2[N:4]=[C:5]3[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N:6]3[CH:12]=2)[CH2:25][CH2:26]1
Reactant: Cc1cccn2cc(CCl)nc12
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccn2cc(CN3CCN(c4ccc(Cl)cc4Cl)CC3)nc12
Temperature: 75 °C

Procedure:
A mixture of 2-(chloromethyl)-8-methylimidazo[1,2-a]pyridine (Example 54, Step 1; 0.294 g), 1-(2,4-dichlorophenyl)piperazine (Example 31, Step 1; 0.396 g) diisopropylethylamine (0.35 mL), and THF (2 mL) is heated at 75° C. for 5 hours. The mixture is then concentrated under reduced pressure, partitioned between saturated aq. sodium bicarbonate and dichloromethane, and the combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96) and the appropriate fractions are combined and concentrated to give 2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]-8-methylimidazo[1,2-a]pyridine. The maleic acid salt is formed by adding maleic acid (0.101 g) to the product dissolved in dichloromethane/methanol. Crystallization from dichloromethane/ether gives 0.2192 g of the title compound; mp 151-152° C.; MS m/z 374, 376; IR (mineral oil) 1482, 1345, 1570, 1357, 867 cm-1 ; 1H NMR (CDCl3) δ2.61, 2.80, 3.09, 3.85, 6.67, 6.95, 7.18, 7.35, 7.56, 7.95.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:13][C:14](=[O:16])[CH3:15].F[B-](F)(F)F.[O:22]=[N+:23]=[O:24].O>C(#N)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4]([N+:23]([O-:24])=[O:22])=[CH:5][CH:6]=[C:7]2[NH:13][C:14](=[O:16])[CH3:15]
Reactant: O=[N+]=O
Reactant: CC(=O)Nc1cccc2c(Br)ccc(C)c12
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1ccc([N+](=O)[O-])c2c(Br)ccc(C)c12

Procedure:
To a cold (-5° C.) suspension of 4.45 g (16.00 mmol) of compound (19) in 25 ml acetonitrile was added dropwise a suspension of 2.60 g (16.64 mmol) of nitronium tetrafluoroborate in 5 ml of acetonitrile. After ten minutes, the homogenous, light-yellow reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated NaCl solution and then dried over anhydrous MgSO4. The solvent was then removed under reduced pressure, and the crude residue was recrystallized from methanol to give N-(5-bromo-8-methyl-4-nitro-naphthalen-1-yl)-acetamide (20) as a light-yellow solid, m.p. 216°-217° C. Another 0.80 g of compound (20) was obtained from the concentrated mother liquors after flash chromatography on silica, eluting hexanes:ethyl acetate (1:1). The overall yield was 2.00 g (39%).
Reaction SMILES: N1C=CC=CC=1.[C:7]([C:10]1[CH:11]=[N:12][C:13]([OH:16])=[CH:14][CH:15]=1)(=O)[CH3:8].Cl.[NH2:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]2[S:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])=[CH:25][CH:24]=1>C(O)C>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([C:7](=[N:18][O:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:35][CH:36]=2)[CH3:8])=[CH:11][N:12]=1
Reactant: CC(=O)c1ccc(O)nc1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(O)nc1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
124 μl of pyridine were added at room temperature to a suspension of 100 mg of 3-acetyl-6-hydroxypyridine and 232 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in step (e) above] in 10 ml of ethanol, and the resulting mixture was stirred and heated under reflux for 1 hour. At the end of this time, the reaction mixture was cooled to room temperature and the precipitate was collected by filtration to give 183 mg of the title compound as a crystalline powder, melting at 240-242° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.O>[CH2:25]([N:1]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:7][CH2:6]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
Tert-butyl 4-[(2S)-3-amino-2-hydroxy-propyl]piperazine-1-carboxylate 7c (5 g, 19.30 mmol), potassium carbonate (10.70 g, 77.20 mmol) and benzyl bromide (7.90 g, 46.30 mmol) were dissolved in 120 mL of the mixture solvent of ethanol and water (V/V=5:1). The reaction solution was heated to 60° C. and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, added with 100 mL of water and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[(2S)-3-(dibenzylamino)-2-hydroxy-propyl]piperazine-1-carboxylate 35a (3.65 g, yield: 43.0%) as a light yellow oil.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(OCC)(=O)C>[CH2:25]([O:24][C:22](=[O:23])[C:21](=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:27])[CH3:26]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C(C)Br
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.9 %

Procedure:
1.6 Kg (6.10 mol) triphenyl phosphine was dissolved in 10 L ethyl acetate and 1.0 Kg of ethyl 2-bromopropionate was added into the above solution. The reaction mixture was stirred at room temperature for 2 days. White solid was filtered off and the precipitate was washed with ethyl acetate. The resulting compound was dissolved in methanol and treated with saturated aqueous potassium carbonate. After stirring for 2 h, the yellow solid was filtered off and washed with water to give 1.5 Kg (75%) of desired product.
Reaction SMILES: [ClH:1].[C:2]([C:4]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)([CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:5]([CH:8](C(OCC)=O)[C:9]([O:11]CC)=O)([CH3:7])[CH3:6])#[N:3].S(=O)(=O)(O)[OH:34]>O>[ClH:1].[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][CH2:19][C:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:5]([CH3:7])([CH3:6])[CH2:8][C:9](=[O:11])[NH:3][C:2]1=[O:34]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C)C(C#N)(CCCN(C)C)c1cccc(OC)c1
Reactant: O=S(=O)(O)O
Agent: Cl
Solvent: O
Product: COc1cccc(C2(CCCN(C)C)C(=O)NC(=O)CC2(C)C)c1
Temperature: 25 °C

Procedure:
A reaction vessel is charged with 11.24 kg of diethyl 2-[2-cyano-5-(dimethylamino)-2-(3-methoxyphenyl)-1,1-dimethylpentyl]propanedioate, monohydrochloride (9), and a solution of 11.46 kg of sulfuric acid (96% w/w) in 90L of water is added. The reaction mixture is refluxed for about 54 h. When the reaction is complete as indicated by thin layer chromatography, the solution is cooled to 25° C. The aqueous solution is washed with 20L of methylene chloride. The aqueous phase is mixed with 40L of methylene chloride and basified with 19L of aqueous ammonium hydroxide (29% w/w) while maintaining the temperature at less than 30° C. After separation of the layers, the aqueous phase is extracted twice with 20-L portions of methylene chloride. The combined organic phase is washed twice with 20-L portions of water and filtered through a layer of diatomaceous earth.
Reaction SMILES: [CH2:1]([C:8]1[N:9]([CH2:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-])=O)=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I.CS[C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[NH:32]>C(O)C.C(OCC)C.[Pd]>[CH2:1]([C:8]1[N:9]([CH2:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([NH:17][C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[NH:32])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=N)c1cccs1
Reactant: CN1CCCC1CCn1c(Cc2ccccc2)cc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: CN1CCCC1CCn1c(Cc2ccccc2)cc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
Compound 4 (125 mg, 0.344 mmol) was dissolved in anhydrous ethanol (7 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon (36.2 mg, 0.034 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography in a solvent system of 2M NH3 in methanol:CH2Cl2, 5:95 shows complete conversion to compound 5, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (7 mL) and the ethanolic solution of the amine 5 is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (127.5 mg, 0.447 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 48 hours, at which time the solution was diluted with diethyl ether (100 ml) resulting in the formation of a off-white precipitate that was collected on a sintered glass funnel and washed with ether. The solid was partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution added to adjust pH to 8-9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95) to afford beige foam 6 (75 mg, 49.3%); 1H NMR (DMSO-d6) δ 7.71 (d, 1H, J=3.7 Hz), 7.58 (d, 1H, J=5.2 Hz), 7.35-7.20 (m, 6H), 7.09 (m, 1H), 6.92 (s, 1H), 6.64 (d, 1H, J=8.5 Hz), 6.23 (brs, 2H), 6.10 (s, 1H), 4.14 (s, 2H), 3.99 (t, 2H, J=8.0 Hz), 2.90 (quintet, 1H, J=4.6 Hz), 2.10 (s, 3H), 2.05-1.97 (m, 2H), 1.91-1.80 (m, 1H), 1.69-1.56 (m, 3H), 1.49-1.35 (m, 2H); ESI-MS (m/z, %): 443 (M+1, 70%), 219 (100%).
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.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:2]3[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]=3)[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCN(c2ccc(F)cc2)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 the 1-(4-fluorophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as a white lyophilisate; MS: [M+H]+=402.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:23][CH:22]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: CC(C)=CCN(c1ccc(I)cc1)c1ncccn1
Product: COC(=O)C(C/C=C/c1ccc(N(CC=C(C)C)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 51.5 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (145 mg) was reacted with N-(4-iodophenyl)-N-(3-methyl-2-butenyl)pyrimidin-2-amine (175 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((3-methyl-2-butenyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (133 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=1/1) was used for purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1.[CH:22]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)([CH3:24])[CH3:23].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH:22]([N:25]1[CH2:30][CH2:29][CH:28]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:9]3([CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:20][CH:19]=2)[CH2:27][CH2:26]1)([CH3:24])[CH3:23]
Reactant: CN1CCN(CC2(c3ccc(O)cc3)CCOCC2)CC1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc(C3(CN4CCN(C)CC4)CCOCC3)cc2)CC1
Yield: 14 %

Procedure:
The title compound (72 mg, 14%) was prepared using 4-{4-[(4-methylpiperazin-1-yl)methyl]tetrahydro-2H-pyran-4-yl}phenol, 1-isopropyl-4-hydroxypiperidine (step 1 of intermediate 21), PPh3 and DIAD similarly to the procedure used for intermediate 55. 1H NMR (400 MHz, CDCl3) δ 1.04 (d, 6H), 1.76-1.90 (m, 4H), 1.96-2.08 (m, 4H), 2.17-2.26 (m, 11H), 2.33-2.38 (m, 4H), 2.69-2.80 (m, 3H), 3.51 (t, 2H), 3.69-3.74 (m, 2H), 4.24 (m, 1H), 6.84 (d, 2H), 7.18 (d, 2H). HRMS ESI+ m/z 416.3268 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]CCOCCO)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH:16]([C:23]1[CH:27]=[C:26]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:37]([CH3:38])=[CH:36][C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:34][C:33]=2[CH3:45])[O:25][N:24]=1)[CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22]>>[C:1]([O:5][C:6]([NH:8][CH:16]([C:23]1[CH:27]=[C:26]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:37]([CH3:38])=[CH:36][C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:34][C:33]=2[CH3:45])[O:25][N:24]=1)[CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOCC(O)c1cc(CCCOc2c(C)cc(-c3ccccc3)cc2C)on1
Reactant: CC(C)(C)OC(=O)NCCOCCO
Product: COCCOCC(NC(=O)OC(C)(C)C)c1cc(CCCOc2c(C)cc(-c3ccccc3)cc2C)on1
Yield: 91 %

Procedure:
Reaction of the bromomethyl compound of example 5 with 5-t-butyloxycarbonylamino-3-oxapentanol using essentially the same method as described in example 5 for Compound 7 gave the adduct, 3-(1-t-butyloxycarbonylamino-3,6-dioxaheptyl)-5-[3-[2,6-dimethyl-4-phenylphenoxy]-propyl]-isoxazole in 91% yield. Trifluoroacetic acid (1 ml) was added to a solution of the adduct (240 mg, 0.46 mmol) in DCM (10 ml) and the reaction was allowed to stir under argon for 2 hours. The reaction was concentrated at vacuum then the crude product was partitioned between brine/sodium bicarbonate (1:1, 20 ml) and ethyl acetate (2×100 ml). The combined organic phase was dried (Na2SO4) and concentrated, the crude product was chromatographed on silica gel (20 g); eluent 92.5:7.5 DCM/(10% ammonia in methanol) to give 3-(1-amino-3,6-dioxaheptyl)-5-[3-[2,6-dimethyl-4-phenylphenoxy]-propyl]-isoxazole (Compound 14) in 71% yield. 1 H nmr (CD3OD): δ=7.5-7.15 (m, 7H); 6.24 (s, 1H); 4.55 (s, 2H); 3.81 (t, 2H); 3.61 (s, 4H); 3.46 (t, 2H); 3.03 (t, 2H); 2.72 (t, 2H); 2.26 (s, 6H) and 2.16 (m, 2H). MS (ES): (M+H)+ 425.2428 (Calc. C25H32N2O4H=425.2432).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:19].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:19][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:20]
Reactant: COC(=O)CCCCCCCBr
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCO
Product: COC(=O)/C=C/c1c(C#CCCCCO)cccc1OCCCCCCCC(=O)OC
Yield: 67 %

Procedure:
Using the procedure of example 122, (E)-3-[2-hydroxy-6-(6-hydroxy-1-hexynyl)phenyl]-2-propenoic acid methyl ester (example 176) was alkylated with methyl 8-bromooctanoate giving the title compound, in 67% yield, as a colorless oil.