Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[O:23][CH3:24]>[N+](C1C=CC=CC=1)([O-])=O>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:20]2[CH:21]=[C:16]([F:15])[C:17]([O:23][CH3:24])=[CH:18][C:19]=2[F:22])=[O:11])=[CH:8][CH:7]=1
Reactant: COc1cc(F)ccc1F
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(F)c(C(=O)c2ccc(Br)cc2)cc1F
Temperature: 25 °C

Procedure:
75 ml of nitrobenzene are cooled in an ice bath and treated in succession 25 with 17.3 g of aluminium chloride and 4-bromobenzoyl chloride in 25 ml of nitrobenzene at a maximum 6° C. The mixture is stirred for 10 min., whereupon 15.7 g of 2,5-difluoroanisole are added in such a manner that the temperature does not exceed 6° C. The solution is left to warm to room temperature overnight, then poured on to ice-water and extracted with methylene chloride. The organic phase is washed with water and 10% sodium chloride solution, dried over sodium sulphate and concentrated. After crystallization from cyclohexane there are obtained 28.4 g of (4-bromo-phenyl)-(2,5-difluoro-4-methoxy-phenyl)-methanone.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=C[C:8]([NH:12]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH3:23]>>[NH2:23][C:8]1[CH:9]=[CH:10][C:11]2[C:6](=[CH:5][CH:4]=[N:3][CH:2]=2)[N:12]=1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc3c(Cl)nccc3c2)cc1
Product: Nc1ccc2cnccc2n1
Yield: 89.73 %

Procedure:
2-Chloro-1,6-naphthyridine (0.628 g, Production Example 22b) and an aqueous ammonia (40 ml) were heated at 130° C. for 11 hours in a sealed tube. After cooling, the mixture was extracted with ethyl acetate, and the extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column, to give the title compound (0.497 g, 89.73%) as pale yellow crystals.
Reaction SMILES: Cl[Si:2]1([CH3:6])[CH2:5][CH2:4][CH2:3]1.[C:7]([O:10][Si](C)(C)C)([CH3:9])=[CH2:8]>>[CH3:6][Si:2]1([O:10][C:7]([CH3:9])=[CH2:8])[CH2:5][CH2:4][CH2:3]1
Reactant: C=C(C)O[Si](C)(C)C
Reactant: C[Si]1(Cl)CCC1
Product: C=C(C)O[Si]1(C)CCC1

Procedure:
In accordance with the general procedure of Example 1, when 1-chloro-1-methylsilacyclobutane and isopropenoxytrimethylsilane are reacted it is predicted that the title compound is obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:28][CH2:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=[O:39])[N:34]([CH:40]1[CH2:45][CH2:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])[CH2:33]2.O>CN(C=O)C>[O:47]=[C:41]1[CH:40]([N:34]2[CH2:33][C:32]3[C:36](=[CH:37][CH:38]=[C:30]([CH2:29][NH:28][C:10](=[O:12])[CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:13])=[CH:8][CH:7]=4)[CH:31]=3)[C:35]2=[O:39])[CH2:45][CH2:44][C:43](=[O:46])[NH:42]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(C(F)(F)F)cc1)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 2 h
Yield: 29.9 %

Procedure:
A mixture of (α,α,α-trifluoro-p-tolyl) acetic acid (0.33 g, 1.6 mmol) and CDI (0.27 g, 1.7 mmol) was stirred in DMF (20 ml) at 40° C. under N2 for 2 hours. After 2 hours, 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol) was added. After 2 h, TEA (0.16 g, 1.6 mmol) was added to the mixture and stirring continued for 16 h at this temperature. Water (40 mL) was added, resulting in precipitation of the product. The solids were filtered, washed with water (50 mL) and dried in vacuo providing N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-2-(4-trifluoromethyl-phenyl)-acetamide as an off-white solid (0.22 g, 29% yield); mp 217-219° C.; HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.95 (96.06%); 1H NMR (DMSO-d6) δ 1.98-2.02 (m, 1H), 2.32-2.46 (m, 1H), 2.57-2.63 (m, 1H), 2.86-2.98 (m, 1H), 3.63 (s, 2H), 4.25 (d, 1H, J=17.4), 4.31-4.45 (m, 3H), 5.11 (dd, 1H, J=13.2, J=5.1), 7.37-7.43 (m, 2H), 7.51 (d, 2H, J=7.8), 7.67-7.70 (m, 3H), 8.74 (t, 1H, J=5.7), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 41.9, 42.3, 47.0, 51.6, 122.0, 122.9, 124.4 (q, J=269.3), 125.0 (q, J=3.75), 127.1, 127.2 (q, J=31.5), 129.9, 130.4, 141.1, 142.3, 143.6, 167.9, 169.5, 171.0, 172.9; LCMS: MH=460; Anal. Calcd for C23H20F3N3O4+0.5 CH2Cl2: C, 56.24; H, 4.22; N, 8.37. Found: C, 56.10; H, 3.92; N, 8.50.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:20][CH2:21][CH2:22][O:23][C:24]1[C:31]([CH3:32])=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[CH3:33]>C(O)C.[Cu](Cl)Cl>[OH:20][CH2:21][CH2:22][O:23][C:24]1[C:31]([CH3:32])=[CH:30][C:27]([C:28]2[N:6]([C:7]3[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=3)[C:4](=[O:5])[C:3]3[C:2](=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:1]=2)=[CH:26][C:25]=1[CH3:33]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: CC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Agent: Cl[Cu]Cl
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(C(C)C)cc2)cc(C)c1OCCO

Procedure:
To a solution of 2-amino-N-(4-isopropylphenyl)benzamide (0.400 g, 1.57 mmol) and 4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde (0.30 g, 1.57 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.63 g, 4.71 mmol). The reaction mixture was stirred at reflux for 4 hours under nitrogen. The solvent was removed and the residue was diluted with dichloromethane (150 mL) and water (100 mL). The organic phase was separated and further washed with water (100 mL), brine (100 mL), and dried over sodium sulfate. The crude mixture was purified by column chromatography on silica gel (230-400 mesh) using hexane/ethyl acetate (1:1) as eluent to give the title compound as a white solid. Yield: 100 mg (15.6%). MP 160-162° C. 1H-NMR (400 Hz, CDCl3): δ 8.34 (d, J=7.6 Hz, 1H), 7.80 (m, 2H), 7.52 (m, 1H), 7.17 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 6.97 (s, 2H), 3.90 (m, 2H), 3.78 (t, J=4.8 Hz, 2H), 2.86 (m, 1H), 2.13 (s, 6H), 2.06 (t, J=6.4 Hz, 1H), 1.20 (d, J=7.2 Hz, 3H). MS (ES+) m/z: 429.52 (M+1).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:45][CH2:46][CH2:47][N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>C1COCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:45][CH2:46][CH2:47][N:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)=[O:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: NCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCN1CCCC1)c1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 4-([1,1′-biphenyl]-4-ylmethoxy)benzoic acid (3 g) in THF (200 ml) were added WSC (2 g) and HOBt (1.5 g) followed by the addition of 1-(2-aminoethyl)pyrrolidine (1.1 g). After stirring at room temperature for 30 min, triethylamine (2 ml) added to the reaction mixture, which was stirred at room temperature for additional 72 hr. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous potassium carbonate and water sequentially, dried, and concentrated. The residue was recrystallized from ethanol/ethyl ether to obtain the titled compound (2.7 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[OH:8])=[O:4].[N-:19]=[N+:20]=[N-:21].[Na+]>>[N:19]([CH2:2][C:3]([NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[OH:8])=[O:4])=[N+:20]=[N-:21]
Reactant: COc1ccc(OC)c(C(O)CNC(=O)CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1ccc(OC)c(C(O)CNC(=O)CN=[N+]=[N-])c1

Procedure:
The synthesis of Midodrine HCl consists of reacting the key intermediate (2) with chloroacetyl chloride to afford 2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide (3). The reaction of (3) with sodium azide will provide 2-azido-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide (4) which is subsequently subjected to hydrogenation to afford Midodrine base (6).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:4]1>CCOC(C)=O.[Pd]>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: COC1CCN(c2ccc([N+](=O)[O-])cn2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1CCN(c2ccc(N)cn2)C1
Reaction time: 8 h

Procedure:
This nitro compound was dissolved in 10 mL of EtOAc, and treated with 100 mg of 10% palladium on carbon. The reaction was shaken under 50 psi of H2 overnight. The reaction was filtered through a celite pad, and the filtrate was concentrated to afford 6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-ylamine, which was used directly in the next step without further purification. LRMS calcd for C10H15N3O (m/e) 193, obsd 194 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[S:13]([N:16]([C:25]1[C:30]([O:31][CH3:32])=[N:29][C:28](Cl)=[C:27]([Cl:34])[N:26]=1)COCC[Si](C)(C)C)(=[O:15])=[O:14]>>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[S:13]([NH:16][C:25]1[C:30]([O:31][CH3:32])=[N:29][C:28]([NH:1][CH2:2][CH2:3][OH:4])=[C:27]([Cl:34])[N:26]=1)(=[O:14])=[O:15]
Reactant: NCCO
Reactant: COc1nc(Cl)c(Cl)nc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Product: COc1nc(NCCO)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 67 using 2-aminoethanol (0.05 g) and 2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (0.1 g). Yield 0.015 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Na].[CH3:16][CH:17]([C:19]1[N:23]([CH2:24][CH2:25][C@@H:26]([OH:34])[CH2:27][C@@H:28]([OH:33])[CH2:29][C:30](O)=[O:31])[C:22]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[C:21]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:20]=1[C:48]([NH:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:49])[CH3:18].CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[F:41][C:38]1[CH:37]=[CH:36][C:35]([C:22]2[N:23]([CH2:24][CH2:25][C@@H:26]([OH:34])[CH2:27][C@@H:28]([OH:33])[CH2:29][C:30]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:31])[C:19]([CH:17]([CH3:18])[CH3:16])=[C:20]([C:48](=[O:49])[NH:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:21]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:40][CH:39]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Reactant: CC(C)(C)OC(=O)NCCOCCN
Agent: CCN=C=NCCCN(C)C
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)NCCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 2-(2-aminoethoxyl)ethylcarbamate (150 mg, 0.735 mmol) is then taken up in CH3CN (10 mL) along with the sodium salt of atorvastatin (0.735 mmol) and EDCI (155 mg, 0.81 mmol). The resulting reaction mixture is stirred at room temperature for 18 h. It is then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-((3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanamido)ethoxy)ethylcarbamate.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[C:3]3[N:4]([CH:12]=[CH:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Clc1nc2ccccc2n2ccnc12
Reactant: C1CCNCC1
Product: c1ccc2c(c1)nc(N1CCCCC1)c1nccn12

Procedure:
By reaction of 4-chloroimidazo[1,2-a]quinoxaline (example 1) with piperidine, according to a procedure that is similar to that followed in example 3, there is obtained 4-(1-piperidinyl)imidazo[1,2-a]quinoxaline. m.p. (DSC)=108.2° C.(onset); IR (KBr): 3107, 2935, 1517 cm-1 ; 1H NMR (CDCl3): δ7.9 (1H,d, J=2 Hz), 7.75÷7.4 (3H,m), 7.4÷7.1 (2H,m), 4.3 (4H,t), 1.9÷1.6 (6H,m), 7.75÷7.4 (3H,m), 7.4÷7.1 (2H,m), 4.3 (4H,t) 1.9÷1.6 (6H,m); UV (EtOH): λmax =231, 249, 293, 305, 333 nm. Elementary analysis for C15H16N4 (m.w.252.32): calcd. C 71.40, H 6.39, N 22.20%; found C 71.38, H 6.63, N 22.61%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][Zn+].NC1C=CC(CC2C=CC=CC=2)=CC=1C#N>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH3:12])[CH:15]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(I)ccc1N
Reactant: COc1cccc(C[Zn+])c1
Agent: N#Cc1cc(Cc2ccccc2)ccc1N
Agent: [Cl-]
Product: COc1cccc(Cc2ccc(N)c(C#N)c2)c1

Procedure:
From 9 (488 mg, 2 mmol) and 3-methoxybenzylzinc chloride (0.5 M in THF, 10 mL, 5 mmol) by the same method as 10a; white powder (274 mg, 49%): mp 81-82° C.; 1H NMR (CDCl3) δ 3.81 (s, 2H, OMe), 3.82 (s, 2H, CH2), 4.25 (br s, NH2), 6.67 (d, J=8.0 Hz, 1H, H-3), 6.68 (s, 1H, H-2′), 6.72-6.77 (m, 2H, H4′ and H-6′), 7.15 (d, J=8.0 Hz, H-4), 7.19 (s, 1H, H-6), 7.22 (t, J=7.6 Hz, 1H, H-5′).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][CH:5]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7].[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH3:31])(=O)=O.[ClH:39]>C1(C)C=CC=CC=1.CC(C)=O>[ClH:39].[ClH:39].[CH3:31][O:7][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:5]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[CH2:4][CH2:3][CH:2]([CH3:24])[CH3:1]
Reactant: CC(C)CCC(NCCCN1CCCCC1)C(O)c1ccccc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: COC(c1ccccc1)C(CCC(C)C)NCCCN1CCCCC1
Yield: 21 %

Procedure:
To a solution of (1RS,2SR)-5-methyl-1-phenyl-2-(3-piperidinopropylamino)hexan-1-ol (1.66 g, 5 mmol) in toluene (25 ml) was added sodium hydride (0.14 g, 6 mmol) and the mixture was refluxed for 1 hour. To the reaction mixture was added methyl tosylate (1.12 g, 6 mmol) and the resulting mixture was refluxed for further 1 hour. After being cooled, the mixture was washed twice with water and once with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by neutral alumina column chromatography (alumina: 40 g, eluent: chloroform) to give 1.1 g of oily matter. To a solution of the matter in acetone (20 ml) was added concentrated hydrochloric acid (0.1 ml) and the mixture was concentrated under reduced pressure. The residue was recrystallized from acetone (10 ml)-ethanol (0.2 ml) to obtain 0.45 g of the title compound as white crystals (yield: 21%).
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[C:4]([N+:10]#[C-:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[O:14]([C@H:21]1[CH2:26][CH2:25][C@H](N)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)CCC>[O:14]([C@H:21]1[CH2:26][CH2:25][C@H:12]([N:2]2[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:10]=[CH:11]2)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@H]1CC[C@H](Oc2ccccc2)CC1
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCOC(=O)c1cn([C@H]2CC[C@H](Oc3ccccc3)CC2)cn1
Temperature: 150 °C
Reaction time: 3.25 h

Procedure:
Ethyl 3-(dimethylamino)-2-isocyanoacrylate (0.70 g) and the compound (1.14 g) obtained in Step 2 of this Reference Example were dissolved in n-butanol (7.0 mL). Then, to the solution, triethylamine (0.70 mL) was added at room temperature, and the mixture was stirred at 150° C. for 3.25 hours. The reaction solution was concentrated and then purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=50/50-ethyl acetate) to obtain the title compound (0.28 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)=[O:12].OC1C=C(C(=O)/C=C/C2C=CC=CC=2)C=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[C:11](=[O:12])[CH2:10]1
Reactant: O=C(/C=C/c1ccc(F)cc1F)c1cccc(O)c1
Agent: O=C(/C=C/c1ccccc1)c1cccc(O)c1
Product: O=C1CC(c2ccc(F)cc2F)c2ccc(O)cc21
Reaction time: 16 h
Yield: 83 %

Procedure:
The procedure of Step 2 of Example 1 was repeated except for using (E)-3-(2,4-difluorophenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one obtained in Step 1 as a starting material instead of (E)-1-(3-hydroxyphenyl)-3-phenylprop-2-en-1-one and being stirred for 16 h to obtain the title compound (83%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH2:14].CC(O)=O.[O-:20][C:21]#[N:22].[K+].[O-]C#N>O>[NH2:22][C:21]([NH:14][C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:4]=1[C:3]([O:2][CH3:1])=[O:15])=[O:20]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)OC)c(NC(N)=O)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a 1 L flask charged with 2-aminoterephthalic acid dimethyl ester (29.4 g, 141 mmol) was added AcOH (160 mL) and the suspension heated to 60° C. until a solution was formed. A solution of potassium cyanate (23.4 g, 288 mmol) in water (50 mL) was then added to the stirred solution at 60° C. Effervescence was seen and a white ppt crashed out immediately, hindering stirring. AcOH was added (70 mL) to aid stirring and the suspension was stirred at 75° C. for 7 hrs. Another 1 eq of cyanate added portion wise (dry). More effervescence was seen and the reaction left for 16 hours at 70° C. The reaction was cooled to 0° C. and the product ppt was filtered off, the flask washed with water to get all product out. The material was washed with water (150 mL) and air dried o/n under vacuum. The crude product was suspended in MeOH (300 mL) and stirred under reflux for 1 hour. The suspension was cooled to room temperature and filtered. The product was washed with cold MeOH (300 mL) and ether and dried in vacuo to afford the title compound as a white solid, 31.5 g, 89%. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.71 (1H, s) 8.97 (1H, s) 7.98 (1H, d, J=8.08 Hz) 7.46-7.57 (1H, m) 6.73 (2H, s) 3.88 (6H, s).
Reaction SMILES: [CH3:1][C:2]([S:12]([CH2:15][CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17](O)=[O:18])(=[O:14])=[O:13])([C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:3].C1([N:33]=C=NC2CCCCC2)CCCCC1.C1C=CC2N(O)N=NC=2C=1.N>C(Cl)Cl.CN(C)C=O>[CH3:1][C:2]([S:12]([CH2:15][CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17]([NH2:33])=[O:18])(=[O:14])=[O:13])([C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:3]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C(=O)N1CCOCC1)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C(=O)N1CCOCC1)S(=O)(=O)CC(Cc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Analogously to the procedure described by Wang et al. in Synthesis 1989, 37 a mixture of 15.34 g (40mmol) of (S)-α-[[[(1-methyl-1-(morpholinocarbonyl)ethyl]sulfonyl]methyl]hydrocinnamic acid, 9.29 g (40 mmol) of dicyclohexylcarbodiimide and 6.89 g (50 mmol) of HOBT in 160 ml of methylene chloride and 40 ml of dimethylformamide was stirred at room temperature for 4 hours. Thereafter, the reaction mixture was filtered, the yellowish solution obtained was diluted with 200 ml of methylene chloride and cooled to 0°. Ammonia was conducted into this solution until it was saturated. The suspension obtained was stirred at room temperature for 1 hour. Subsequently, the solid formed was filtered off under suction and washed with 100 ml of methylene chloride. The yellow coloured filtrate was then washed twice with in each case 200 ml of water and twice with 200 ml of saturated sodium chloride solution. The wash solutions were extracted with 500 ml of methylene chloride. The combined organic phases were dried over sodium sulphate and thereafter evaporated under reduced pressure. For purification, the yellowish crude product obtained (15.3 g) was chromatographed on 1.3 kg of silica gel using a 4:1 mixture of ethyl acetate and hexane as the eluent. There were obtained 13.6 g of (S)-α-[[[(1-methyl-1-(morpholinocarbonyl)ethyl]sulfonyl]methyl]hydrocinnamamide as a colourless powder, MS: 383 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CO.C(Cl)(Cl)Cl.[I-]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: C[Sn](C)(C)c1ccncc1
Reactant: CC(=O)NCC1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccncc3)c(F)c2)C(=O)O1

Procedure:
A slurry of (±)-N-[[3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide (PREPARATION 18, 0.063 g, 0.165 mmol) and trimethyl(4-pyridyl)tin (0.060 g, 0.248 mmol) in 1,4-dioxane (5 ml) is degasseal by repeated evacuation and filling with nitrogen. Bis(triphenylphosphine)palladium (II) chloride (0.012 g, 0.0165 mmol) is added, the reaction again alegassed, and then the mixture is brought to reflux under nitrogen. After 4 hr TLC (silica gel, 10% methanol/chloroform) reveals some of the iodide still remains. The mixture is refluxed a further 20 hr, cooled to 20°-25°, and concentrated under reduced pressure. The residue is chromatographed over silica gel, eluting with a litfie chloroform and then methanol/chloroform (1%, 2%, and then 5%). The appropriate fractions are pooled and concentrated to give the enantiomerically enriched title compound, mp 190.5°-191.0°; [ct]25 -16.4 ° (c 0.5, CHCl3). The following characteristics are noted for a racemic sample, mp 179°-180°; IR (internal reflectance) 3279, 3063, 1756, 1752, 1657, 1626, 1600, 1542, 1522, 1485, 1412, 1407, 1377, 1222, 1198 cm-1 ; NMR (CDCl3, 300 MHz) 8.67, 7.59, 7.50, 7.47, 7.33, 6.15, 4.84, 4.11, 3.85, 3.78-3.62, 2.04 δ; MS (m/z) 329 (39.8, M+), 285, 257, 201,172, 73 and 42. ##STR3## .