Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=O)[CH2:17][CH2:16][CH2:15]2)#[N:11].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)=[CH:17][CH2:16][CH2:15]2)#[N:11]
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc2c(c1)CCCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc2c(c1)CCC=C2n1ccnc1
Reaction time: 7 h

Procedure:
175 μl of thionyl chloride are added dropwise to a solution of 272 mg of imidazole in 2.5 ml of methylene chloride. 342 mg of 6-cyano-1-tetralone are added in portions to the resulting white suspension, and the reaction mixture is stirred for 7 hours at 40° and then for 24 hours at room temperature. 386 mg of potassium carbonate in 1.6 ml of water are added to the reaction mixture, which is then extracted with chloroform. After drying the organic phase over sodium sulfate, concentration is carried out under reduced pressure. The resulting crude product is purified by column chromatography (0.04-0.063 mesh SIO2, hexane/ethyl acetate 1:2). Crystallisation from ether yields the title compound in the form of colourless crystals; m.p. 152°-153°. TLC (ethyl acetate): Rf=0.17.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].ClC1C=CC(C2C=CC([C@H]3CC[C@H](CC[C@H]4CC[C@H](CCCCCC)CC4)CC3)=CC=2)=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)[C:62]([Cl:64])=[O:63]>C(Cl)Cl.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:62]([Cl:64])=[O:63])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCc1ccc([C@H]2CC[C@H](CCc3ccccc3)CC2)cc1
Agent: CCCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(Cl)cc4)cc3)CC2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCc1ccc([C@H]2CC[C@H](CCc3ccc(C(=O)Cl)cc3)CC2)cc1
Temperature: 0 °C

Procedure:
After 27.6 g of the (2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)benzene obtained in (7) of Example 2 was dissolved in 200 ml of methylene chloride, it was cooled down to 0° C., and 24 g of aluminum chloride was added to the solution and stirred. Oxalyl chloride in an amount of 22.8 g was added dropwise little by little to the solution, and after the temperature of the solution was raised up to room temperature, it was stirred for 2 hours. After finishing of the reaction, it was added to 500 ml of water and extracted with 200 ml of methylene chloride. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 20 g of 4-(2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)benzoyl chloride.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH:12]([C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)O.CS(O)(=O)=O.[OH-].[Na+]>O>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:9][CH2:10][CH2:11][CH:12]2[C:14]1[N:15]=[CH:16][NH:17][CH:18]=1
Reactant: OC(CCCc1ccccc1Cl)c1c[nH]cn1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Clc1cccc2c1CCCC2c1c[nH]cn1
Temperature: 100 °C

Procedure:
A mixture of 4-(2-chlorophenyl)-1-(1H-imidazol-4-yl)-butan-1-ol hydrochloride (1.0 g) and methanesulfonic acid (15 ml) is heated at 100° C. for 2 hours. The cooled reaction mixture is poured into water and is made alkaline with sodium hydroxide solution. The product is extracted into ethyl acetate which is washed with water, dried with sodium sulfate and evaporated under reduced pressure. The crude product is recrystallized from ethyl acetate. The yield is 0.4 g, m.p. 165-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH3:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17]>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(Cl)ccc1I
Reactant: Sc1ccccc1Br
Product: Cc1cc(Cl)ccc1Sc1ccccc1Br

Procedure:
Prepared from 4-chloro-1-iodo-2-methyl-benzene and 2-bromo-benzenethiol.
Reaction SMILES: [NH2:1][C:2](=[O:16])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10](Cl)[N:9]=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=1)[CH3:4].[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:29][NH:28][CH2:27]2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2](=[O:16])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10]([N:28]2[CH2:29][CH:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:30])[F:31])=[CH:25][CH:24]=3)[CH2:27]2)[N:9]=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=1)[CH3:4]
Reactant: FC(F)(F)Oc1ccc(C2CNC2)cc1
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](Nc1cc(C(N)=O)nc(N2CC(c3ccc(OC(F)(F)F)cc3)C2)n1)C(N)=O
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A mixture of (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (compound 37-6) (243 mg, 1 mmol), 3-(4-(trifluoromethoxy)phenyl)azetidine (1 mmol), and K2CO3 (138 mg, 1 mmol) was dissolved in DMF (3 mL), stirred at 80° C. for 14 hr, and then cooled to room temperature. The mixture was extracted with EtOAc (2×20 mL) and dried over MgSO4. After the removal of ethyl acetate via rotary evaporation the residue was subjected to flash chromatography using DCM/MeOH as the eluent to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(3-(4-(trifluoromethoxy)phenyl)azetidin-1-yl)pyrimidine-4-carboxamide (Cpd. No. 101) as a white solid (150 mg). 1H NMR (CD3OD) δ 7.12 (m, 2H), 6.80 (m, 2H), 6.42 (s, 1H), 5.05 (m, 1H), 3.90-4.45 (m, 5H), 1.35 (d, 3H). LC/MS: m/z=425 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:31][CH2:32][C@@H:33]1[C@@H:37]([CH3:38])[NH:36][C:35](=[O:39])[CH2:34]1.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>CC(N(C)C)=O>[CH3:38][C@H:37]1[NH:36][C:35](=[O:39])[CH2:34][C@@H:33]1[CH2:32][NH:31][C:15]1[N:14]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2
Reactant: COc1cc(-c2cc3ncccc3c(OS(=O)(=O)C(F)(F)F)n2)cc(OC)c1OC
Reactant: C[C@H]1NC(=O)C[C@@H]1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2cc3ncccc3c(NC[C@H]3CC(=O)N[C@@H]3C)n2)cc(OC)c1OC
Temperature: 80 °C

Procedure:
100 mg 6.1 and 33 mg (4R,5R)-4-(aminomethyl)-5-methylpyrrolidine-2-one (2.26) were dissolved in dimethylacetamide. 0.175 mL Diisopropylethylamine was added and the mixture was heated at 80° C. for 85 min. The mixture was acidified with trifluoroacetic acid and purified via chromatography (RP-HPLC) and the corresponding fractions were freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:8])[CH2:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:11]=1
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)CC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 102.4 %

Procedure:
30 g of methyl 4-chlorobenzoate was dissolved in anhydrous THF, and 16.9 g of 60% sodium hydride was added under cooling with ice. 21.1 g of pinacolone was added dropwise, and the mixture was stirred under heating at 50° C. for 6 hours. Then, 100 ml of water was added dropwise under cooling with ice, and the solvent was distilled off under reduced pressure. 200 ml of water and 100 ml of 6N hydrochloric acid were added thereto, and then extraction with ethyl acetate was carried out. The extract layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: chloroform/hexane=2/8) to obtain 43 g of the desired product as a viscous liquid. nD20.0 1.5012
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CC(C)=O.O>[O:1]([CH2:8][CH2:9][C:10]([N:13]=[N+:14]=[N-:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)CCOc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)CCOc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
Phenoxypropionyl chloride (9.23 g, 0.05 mol) is dissolved in 100 ml acetone and cooled with an ice bath as sodium azide (3.6 g, 0.055 mol) in 10 ml water is added dropwise. After addition is completed, the reaction mixture is warmed to room temperature and stirred for 30 minutes. The solution is decanted and concentrated. The residue is dissolved in 100 ml ether and washed with saturated sodium bicarbonate and brine. The organic phase is separated, dried (MgSO4) and concentrated to give 6.52 g (68.0% yield) of phenoxypropionyl azide as a yellow oil which solidifies on cooling. IR (KBr) cm-1 : 2137 (N3), 1718 (C=O); 1H nmr (CDCl3) δ: 7.31 (m, 2H, phenyl H), 6.98 (t, 1H, J=7.5 Hz, phenyl H), 6.92 (m, 2H, phenyl H), 4.26 (t, 3H, J=6.3 Hz, CH2O), 2.84 (t, 3H, J=6.3 Hz, CH2C=O); 13C nmr (CDCl3) δ: 178.0, 159.0, 129.5(2C), 121.2, 114.7(2C), 62.9, 36.9.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:3][N:2]=1.[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:28][N:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:30]=3)[CH2:32][CH2:33]2)=[O:19])=[CH:3][N:2]=1
Reactant: O=C(Nc1cncc2ccccc12)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cncc2ccccc12)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 28.5 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl isoquinolin-4-ylcarbamate (236 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 87.7 mg (28.5%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]([OH:7])=[O:6].[H-].[Na+].[CH3:30]I.O>CN(C)P(N(C)C)(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]([O:7][CH3:30])=[O:6]
Reactant: CI
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1F
Reaction time: 1 h

Procedure:
A solution of 7.20 g of 3-fluoro-4-(hexadecylamino)benzoic acid in 25 ml of hexamethylphosphoramide is added to a stirred mixture of 0.800 g of sodium hydride (57% in mineral oil) and 25 ml of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g of methyl iodide and is then stirred at 25° C. for 18 hours Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield methyl 3-fluoro-4-(hexadecylamino)benzoate as a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][O:9][C:8]=2[CH:15]=1.Cl.[CH3:17][O:18][C:19](=O)[O:20]C>>[CH3:17][O:18][C:19]([CH:12]1[CH2:11][CH2:10][O:9][C:8]2[CH:15]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=2[C:13]1=[O:14])=[O:20]
Reactant: COC(=O)OC
Reactant: O=C1CCCOc2cc(F)ccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCOc2cc(F)ccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
A suspension of sodiumhydride in parrafin (0.49 g, 60%) was added to 5 ml dimethylcarbonate. To this suspension 8-Fluoro-3,4-dihydro-2H-benzo[b]oxepin-5-one (6.2 mmol) dissolved in 2 ml dimethylcarbonate was added dropwise at room temperature. The mixture was refluxed for two hours, cooled to room temperature and stirred overnight. 25 ml of 2 mol/l hydrochloric acid were added to the mixture. The resulting solution was extracted by ethyl acetate. The organic phase was dried over sodiumsulfate and the solvent removed in vacuo. The residue was dissolved in diethyl ether. 8-Fluoro-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid methyl ester was obtained by crystallization from this solution in a yield of 7%. LC-MS: 1.8 min, 238.0 (MH+), 2.4 min, 238.0 (MH+)
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([CH2:26][C:27]3[CH:39]=[CH:38][C:30]4[O:31]C(C)(C)[O:33][C:34](=[O:35])[C:29]=4[CH:28]=3)[C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CCO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([CH2:26][C:27]3[CH:39]=[CH:38][C:30]([OH:31])=[C:29]([CH:28]=3)[C:34]([OH:35])=[O:33])[C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc2c(c1)C(=O)OC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(O)c(C(=O)O)c1

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-[(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)methyl]hexanamide and NaOH 5N in the presence of EtOH as a yellow powder (79%). 1H NMR (CDCl3, 300 MHz) δ 10.85 (s, 1H), 7.90-6.95 (m, 11H), 4.64-4.43 (m, 4H), 2.64 (t, J=7.5 Hz, 2H), 2.48 (m, 2H), 1.75 (m, 2H), 1.62 (m, 2H), 1.33 (m, 6H), 0.94 (t, J=7.2 Hz, 3H), 0.88 (m, 3H). M− (ESI): 510.3; M+ (ESI): 512.4. HPLC, Rt: 5.6 min (Purity: 99%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:13])=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=O.[OH-].[K+].C1(C)C=CC(S(O)(=O)=O)=CC=1>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1C=CC=CC=1>[CH2:1]([C:4]1[C:5]2[O:13][C:17]([C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[F:14])=[CH:11][C:10](=[O:12])[C:6]=2[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1ccccc1F
Reactant: C=CCc1cccc(C(C)=O)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])O
Solvent: c1ccccc1
Solvent: O
Product: C=CCc1cccc2c(=O)cc(-c3ccccc3F)oc12
Temperature: 80 °C
Yield: 58.3 %

Procedure:
A mixture of 0.528 g (3 mmol) of 3'-allyl-2'-hydroxyacetophenone, 0.57 g (3.6 mmol) of 2-fluorobenzoyl chloride, 0.509 g (1.5 mmol) of tetra-n-butylammonium bisulfate, 20 ml of 10% aqueous potassium hydroxide and 20 ml of benzene was heated at 80° C. for 3 hours. The layers were separated and the benzene layer washed thoroughly with water (3×20 ml) and the water removed from the benzene layer by azeotropic distillation. The resulting residue was treated with 1.7 g (9 mmol) of p-toluenesulphonic acid and benzene (25 ml) and heated for two hours with azeotropic removal of water. The benzene solution was washed with 8% aqueous sodium bicarbonate (50 ml) and the solvent evaporated in vacuo. The resulting residue was recrystallized from ethyl acetate to give 0.49 g (58%) of 8-allyl-2-(2-fluorophenyl)-4H-benzopyran-4-one as white solid: M.P. 78°-81° C.; TLC R f 0.40 in 10:1 hexane-ethylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N+:10]([O-])=O)[CH:5]=[CH:4][C:3]=1[F:13].[BH4-].[Li+].C[Si](Cl)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][C:3]=1[F:13]
Reactant: O=[N+]([O-])C=Cc1ccc(F)c(Cl)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(F)c(Cl)c1
Yield: 88.5 %

Procedure:
Using the same reaction procedure and workup as described in Example 33, 2-Chloro-1-fluoro-4-(2-nitro-vinyl)-benzene (I-34a: 1.7 g, 8.4577 mmol) in dry THF (17 mL) was reacted with lithium borohydride (736.8 mg, 33.8308 mmol) and trimethylsilyl chloride (8.6 mL, 67.6616 mmol) in dry THF (9 mL) to afford 1.3 g of the product (100% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][OH:24])[CH:19]=[CH:20][C:21]=1[F:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:23][O:24][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1ccc(F)c(Cl)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3ccc(F)c(Cl)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-chloro-4-fluorophenyl)methanol.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[C:15]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)[CH3:18])[CH:14]=[C:13]([CH:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=3)[CH3:28])[CH:12]=2)[CH3:10])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.N#N>O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[C:15]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH3:18])[CH:14]=[C:13]([CH:27]([C:29]3[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=3)[CH3:28])[CH:12]=2)[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)c2cc(C(C)c3ccc(OC)cc3)cc(C(C)c3ccc(OC)cc3)c2)cc1
Agent: Cl
Agent: N#N
Solvent: O
Solvent: c1ccncc1
Product: CC(c1ccc(O)cc1)c1cc(C(C)c2ccc(O)cc2)cc(C(C)c2ccc(O)cc2)c1
Temperature: 180 °C

Procedure:
A 250 mL round-bottomed flask equipped with magnetic stirring bar was charged with racemic 1,3,5-tris(1-(4-methoxyphenyl)ethyl)benzene (5) (19.6 g, 41 mmol) and pyridine hydrochloride (56.8 g, 0.49 mol, 12 equiv). The mixture was protected with an N2 bubbler and heated in a 180° C. oil bath for 5 h. The mixture was allowed to cool briefly to ˜120° C. and then 55° C. H2O (100 mL) was added slowly to the mixture with vigorous stirring. The mixture was extracted three times with EtOAc (100 mL portions). The collected organic phase was washed with brine (200 mL) and dried over anhydrous MgSO4. Rotary evaporation gave a thick, colorless oil that foamed under vacuum. Yield: 17.17 g (95%). 1H NMR (300 MHz, DMSO-d6, δ, ppm): 9.12 (s, 3OH), 6.98 (d, J=8.6 Hz, 6H), 6.90 (s, 3H), 6.63 (d, J=8.6 Hz, 6H), 3.92 (q, J=7.2 Hz, 3H), 1.44 (d, J=7.5 Hz, 9H). 13C NMR (75 MHz, DMSO-d6, δ, ppm): 155.35, 146.59, 146.53, 146.48, 136.69, 136.67, 136.65, 128.04, 123.88, 123.65, 114.96, 43.49, 43.46, 22.09, 22.04. Anal. calcd for C30H30O3.0.65H2O: C, 80.02; H, 7.01. Found: C, 80.38; H, 7.41.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:8])[CH3:2].Br[CH2:18][CH2:19][CH2:20][Cl:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:18][CH2:19][CH2:20][Cl:21])=[CH:13][CH:14]=1)=[O:8])[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)CCC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCC(=O)c1ccc(OCCCCl)cc1

Procedure:
In a 1 L round bottom flask, 4-(4-hydroxyphenyl)-4-oxo-butyric acid ethyl ester (8.65 g, 39.0 mmol), 1-bromo-3-chloro-propane (6.1 g, 61.0 mmol), and potassium carbonate (9.3 g, 67.1 mmol) in acetonitrile (300 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and water, separated and dried over MgSO4. Purification with silica gel chromatography eluting with hexanes/ethyl acetate (3:1) produced 7.9 g (68%). MS m/z 299 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6](O)[C:7]([CH:9]([CH3:11])[CH3:10])=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:21]([O:26]C)([O:24][CH3:25])[O:22][CH3:23]>>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])/[CH:6]=[C:7](\[CH:9]([CH3:11])[CH3:10])/[CH2:8][P:21]([O:24][CH3:25])([O:22][CH3:23])=[O:26])[CH3:2]
Reactant: C=C(C(C)C)C(O)C(NC=O)C(=O)OCC
Reactant: COP(OC)OC
Agent: O=S(Br)Br
Product: CCOC(=O)C(/C=C(/CP(=O)(OC)OC)C(C)C)NC=O

Procedure:
The starting material is manufactured as follows: Reaction of 3-methyl-2-methylene-tutanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(3-methyl-buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which is hydrolysed analogously to Example 15 to 2-formylamino-3-hydroxy-4-isopropyl-4-pentenoic acid ethyl ester. Subsequent treatment with thionyl bromide followed by reaction with trimethyl phosphite analogously to Example 1 yields E-2-formylamino-4-isopropyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].CO.O.[C:14](=S)=[S:15]>>[SH:15][C:14]1[O:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: S=C=S
Reactant: Nc1ncccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Sc1nc2ncccc2o1

Procedure:
A mixture of 2-amino-3-hydroxypyridine and MeOCS2K [prepared from potassium hydroxide (6.2 g), methanol (96 ml), water (17.4 ml) and carbon disulfide (7.1 g)] was refluxed for 20 hr and filtered. The filtrate was neutralized with acetic acid and the resulting precipitate was collected, washed with water and dried to give 2-mercapto-oxazolo[4,5-b]pyridine (8.2 g).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:15])([CH3:14])[C:12]#[CH:13]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][C:11]([OH:15])([CH3:14])[C:12]#[C:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
30 g of 4-bromobenzonitrile, 13.4 g of 3-methyl-1-butyn-3-ol, 0.7 g of triphenylphosphine and 0.3 g of bis(triphenylphosphine) palladium(II) chloride were dissolved in 140 ml of triethylamine in nitrogen atmosphere, and 0.1 g of copper(I) iodide was added thereto. This was stirred for one hour at room temperature and then for 5 hours at 90° C. The crystals as precipitated were filtered out and, after triethylamine was removed by distillation, extracted with chloroform. The crystals were washed two times with 10% hydrochloric acid and two times with water, and chloroform was removed by distillation. The residue was distilled under reduced pressure (b.p. 140° to 160° C./5 mmHg) to obtain 23.5 g of 3-methyl-1-(4'-cyanophenyl)-1-butyn-3-ol.