Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C@H:20]([CH:24]([CH3:26])[CH3:25])[C:21](O)=[O:22])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[NH2:34][OH:35]>C(Cl)Cl.CN(C)C=O.O1CCCC1>[OH:35][NH:34][C:21](=[O:22])[C@H:20]([N:19]([S:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)O)C(C)C)cc1
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NO)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (106 mL, 1.22 mol) is added over 1 hour to dimethylformamide (92 mL) in methylene chloride (1250 mL) at 0° C. To this is added a solution of 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acid hydrochloride (248 g, 0.6 mol) in dimethylformamide (450 mL) over 1 hour, maintaining the temperature at 0° C. This solution is stirred an additional 2 hours at room temperature, and then added dropwise to a mixture of hydroxylamine (460 g of a 50% aqueous solution, 6.82 mol) in tetrahydrofuran (2400 mL). The reaction is stirred an additional 3 hours at 5° C., and then at room temperature overnight. The reaction mixture is filtered, the organic layer is collected, and the solvent is evaporated. The crude product is re-dissolved in methylene chloride (2 L), washed with water (2×1 L), saturated sodium bicarbonate (4×1 L), brine (1 L), dried (Na2SO4), and the solvent is evaporated. The product is dissolved in ethyl acetate (700 mL) and diluted with ether (1400 mL) to induce precipitation. The pure product is collected by filtration to provide N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamide. After conversion to the hydrochloride salt, a white solid is obtained, m.p. 169°-170° C. (dec).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32](O)=[O:33]>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:32](=[O:33])[CH2:31][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Product: O=C(Cc1ccccn1)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 6 except starting with 4-amino-1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine and 2-(2-pyridyl)acetic acid hydrochloride, the title compound was obtained as a white solid (72%), mp 176.0°-7.5° C.; MS(CI): 424 (M+H); NMR (300 MHz,DMSO-d6): 1.37(m, 2H), 1.69(m, 2H), 2.27(m, 2H), 2.45(s, 2H), 2.93(m, 2H), 3.34(m, 2H), 3.57 (m, 3H), 4.31(s, 1H), 6.92(m, 4H), 7.17-7.31(m, 6H), 7.71(t, 1H, J=7.7 Hz), 8.02(d, 1H, J=7.7 Hz), 8.45(m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH3:29][C:30]1[NH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2>>[CH3:29][C:30]1[N:31]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: Cc1cc2ccccc2[nH]1
Product: Cc1cc2ccccc2n1Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1
Yield: 70 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 2-methyl-1-H-indole, the title compound was isolated as a yellow solid in 70% yield (98% purity by HPLC).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]([F:22])[F:21])[CH:18]=[N:19][C:4]=2[CH:3]=1.[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.O.[Cl-].[Na+].O>[F:21][CH:20]([F:22])[N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:32]3[CH:31]=[CH:30][C:29]([N:26]4[CH2:25][CH2:24][O:23][CH2:28][CH2:27]4)=[CH:34][CH:33]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](Oc1nc(-c2ccc(N3CCOCC3)cc2)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Reaction time: 1.75 h

Procedure:
Intermediate 2.64 (24 mg, 0.073 mmol), 4-morpholinophenylboronic acid (33 mg, 0.16 mmol), Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (1.7 mg, 0.0024 mmol) and K3PO4 (52 mg, 0.25 mmol) were taken up in 1,4-dioxane (0.9 mL) under Ar. Water (0.1 mL) was added and the resulting stirred mixture was heated to 100° C. After 1.75 h, the reaction mixture was cooled to r.t. and was diluted with EtOAc (2 mL), water (1 mL), and brine (1 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (4×1.5 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (0% to 15% MeOH in DCM) to afford (R)-4-((R)-1-(3-(difluoromethyl)-6-(4-morpholinophenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.24. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H26F2N5O3: 458.2; found 458.0. 1H NMR (400 MHz, Chloroform-d) δ 8.26 (s, 1H), 7.99-7.88 (m, 2H), 7.72 (s, 1H), 7.61 (t, J=61.1 Hz, 1H), 7.05-6.95 (m, 2H), 6.05 (s, 1H), 5.79-5.67 (m, 1H), 3.94-3.83 (m, 4H), 3.62-3.53 (m, 1H), 3.37 (dd, J=9.7, 6.2 Hz, 1H), 3.28-3.19 (m, 4H), 3.00-2.88 (m, 1H), 2.56 (dd, J=17.2, 9.3 Hz, 1H), 2.45 (dd, J=17.2, 7.4 Hz, 1H), 1.50 (d, J=6.2 Hz, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[CH2:7][CH3:8]>>[Cl:1][CH2:2][C:3]([C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([CH2:6][CH2:7][CH3:8])[CH:10]=1)[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CCCc1cccc2ccc(=O)[nH]c12
Product: CCCc1cc(C(=O)CCl)cc2ccc(=O)[nH]c12

Procedure:
By using chloroacetyl chloride and 8-propylcarbostyril, there was obtained 6-chloroacetyl-8-propylcarbostyril as a white powder having a melting point of 244°-247° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>CCO>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][C:11]([F:10])([F:20])[F:21])=[CH:14][CH:15]=2)[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c(Cl)ncnc1Nc1ccc(OC(F)(F)F)cc1
Yield: 84 %

Procedure:
4,6-Dichloro-5-methylpyrimidine (534.6 mg, 3.3 mmol) and 4-trifluoromethoxy aniline (661 mg, 3.6 mmol) were dissolved in EtOH and DIEA (625 uL, 3.6 mmol) was added and the mixture was refluxed for 4 h. It was then cooled, concentrated and work-up with ethyl acetate. The organic layer was separated and dried (Na2SO4). Concentrated and purified by silica-gel column chromatography (Ethyl acetate/hexane). 800 mg (84% Yield), MS m/z 304.14 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:28](=[O:29])[O:27][C:8]2=[N:9][C:10]([N:13]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]3)=[CH:11][CH:12]=[C:7]2[CH:6]=1)=O.[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>CCO>[S:32]1[CH:33]=[CH:34][N:35]2[CH:2]=[C:3]([C:5]3[C:28](=[O:29])[O:27][C:8]4=[N:9][C:10]([N:13]5[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:15][CH2:14]5)=[CH:11][CH:12]=[C:7]4[CH:6]=3)[N:30]=[C:31]12
Reactant: Nc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc3cc(C(=O)CBr)c(=O)oc3n2)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc3cc(-c4cn5ccsc5n4)c(=O)oc3n2)CC1
Yield: 49.1 %

Procedure:
tert-Butyl 4-(3-(2-bromoacetyl)-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)-1,4-diazepane-1-carboxylate (132 mg, 0.28 mmol) in 5 mL of EtOH was treated with 2-aminothiazole (34.1 mg, 0.34 mmol) at room temperature. The solution was refluxed for 16 hours and concentrated under vacuum. The residue was purified on silica gel to provide tert-butyl 4-(3-(imidazo[2,1-b]thiazol-6-yl)-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)-1,4-diazepane-1-carboxylate (64.3 mg, 49%). MS m/z 468 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[I-:13].[Na+]>C(O)CCC.[Cu]I.CNCCNC>[I:13][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: [I-]
Reactant: Nc1ncc(Br)cc1C(F)(F)F
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CCCCO
Product: Nc1ncc(I)cc1C(F)(F)F
Temperature: 23 °C
Yield: 101.8 %

Procedure:
A mixture of 5-bromo-3-trifluoromethyl-pyridin-2-ylamine (example C.18 step 3) (723 mg, 3 mmol), sodium iodide (900 mg, 6 mmol), copper (I) iodide (29 mg, 5 mol %) and N,N′-dimethylethylendiamine (26 mg, 10 mol %) in n-butanol (6 mL) was stirred at reflux under argon atmosphere for 18 h. The reaction mixture was cooled to 23° C., extracted with ethyl acetate and water, the organic layers were dried over MgSO4, filtered and evaporated to leave the title compound as a brown solid (880 mg, 102%), which was used without further purification. MS (ISN) 287.0 [(M−H)−].
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:18])(=O)=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:10]([C:11]([F:12])([F:13])[F:14])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:18]
Reactant: Nc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Nc1c(Cl)cc(C(=O)O)cc1C(F)(F)F

Procedure:
7.8 g (40 mmol) of 4-amino-5-trifluoromethylbenzoic acid in 80 ml of chloroform are placed in a 500 ml round-bottomed flask in the presence of 9.97 ml (50 mmol) of sulphuryl chloride, and the mixture is stirred under reflux overnight.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16]([NH:17][C:18](=[O:26])[CH2:19][CH2:20]1)=[CH:15][CH2:14]3)[CH3:2]>C(O)(=O)C.[Pt]=O>[CH3:9][C@:8]12[CH2:25][CH2:24][C@H:23]3[C@@H:13]([CH2:14][CH2:15][C@@H:16]4[C@:21]3([CH3:22])[CH2:20][CH2:19][C:18](=[O:26])[NH:17]4)[C@@H:10]1[CH2:11][CH2:12][C@@H:7]2[O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:27]
Reactant: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The product of Step D, above, and platinum oxide (35 mg) in glacial acetic acid (2 ml) was hydrogenated at 40 psi for 22.5 hours. The mixture was filtered through a pad of celite. The filtrate was concentrated and the residue purified via preparative TLC using one silica gel plate (1000μ) developed with EtOAc to give the title product (Rf=0.22; mp 170°-172° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([Br:10])=[CH:4][N:3]=1.[CH2:11]([O:18][C:19]([NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[S:32](Cl)(=[O:34])=[O:33])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH2:11]([O:18][C:19]([NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[S:32]([NH:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([Br:10])=[CH:4][N:3]=1)(=[O:34])=[O:33])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1nc(Br)cnc1N
Reactant: O=C(Nc1cccc2c(S(=O)(=O)Cl)cccc12)OCc1ccccc1
Solvent: CO
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(NC(=O)OCc3ccccc3)cccc12

Procedure:
The starting material 5-(N-benzyloxycarbonylamino)-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide was prepared using an analogous procedure to that described in Example 36, starting from proportionate amounts of 2-amino-5-bromo-3-methoxypyrazine and 5-(N-benzyloxycarbonylamino)-1-naphthalenesulphonyl chloride (obtained as described in Synlett., 1992, 661), in a yield of (11%; m.p. 226-228° C.; mass spectrum (+ve FAB, methanol/NBA): 543 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1>CCCCCC.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: N#CC1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CC(C)O
Solvent: CCCCCC
Product: N#C[C@@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O

Procedure:
1-(2-Cloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (23 g) obtained in Step D of Example 103 was resolved by HPLC (column: CHIRALPAK IC, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=200/800) to give the title compound (12 g: a shorter retention time).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([CH3:25])[CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH:18]([CH3:25])[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1CNC(C)c2ccccc21
Product: CC1CN(C(=O)c2cc3ncc(Cl)cn3n2)C(C)c2ccccc21

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,4-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][NH:22][CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[N:22]([CH3:21])[CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CNC(C)c1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N(C)C(C)c2ccccc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and methyl-(1-phenyl-ethyl)-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C21H25NO5 [M+H]+: 372.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[NH2:10][C:11]([NH2:13])=[O:12].C(OC(=O)C)(=O)C>>[F:1][C:2]([F:9])([F:8])[CH:3]1[CH2:7][NH:13][C:11](=[O:12])[NH:10][C:4]1=[O:5]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: NC(N)=O
Solvent: CC(=O)OC(C)=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1
Temperature: 100 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5 mmoles), urea (300 mg; 5 mmoles) and acetic anhydride (2 ml) was heated at 100° C. with stirring for 1 hour. After cooling to 0° C., the precipitated solid was filtered off to give 450 mg (yield: 40%) of 5-trifluoromethyl-5,6-dihydrouracil. The solvent was evaporated under reduced pressure from the filtrate, and the residue was recrystallized from ethanol to give additional 160 mg (yield: 27%) of 5-trifluoromethyl-5,6-dihydrouracil. The total yield of the product was 67%.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]2)=[N:22][CH:23]=1>N1C=CC=CC=1>[O:4]([C:2]([O:30][CH:27]1[CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[Cl:11])=[CH:19][N:20]=2)[CH2:25][CH2:26]1)=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: OC1CCN(c2ncc(-c3ccccc3Cl)cn2)CC1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)OC1CCN(c2ncc(-c3ccccc3Cl)cn2)CC1
Temperature: 5 °C

Procedure:
11.4 ml of phenyl chloroformate are added slowly to a solution of 12.7 g of 5-(2-chlorophenyl)-2-(4-hydroxypiperidino)pyrimidine (Example 4) in 50 ml of pyridine, cooled to 5° C. After the addition has ended, the mixture is heated at 60° C. for 3 hours.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].[OH-:16].[CH3:17][N+:18]([CH3:21])([CH3:20])[CH3:19]>CO>[CH3:17][N+:18]([CH3:21])([CH3:20])[CH3:19].[F:1][C:2]1[C:7]([S:8]([O-:16])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: [OH-]
Agent: C[N+](C)(C)C
Solvent: CO
Product: O=S(=O)([O-])c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pentafluorobenzenesulfonyl chloride (25 g) was dissolved in 100 ml of methanol with ice-cooling, and 100 g of a 25% aqueous solution of tetramethylammonium hydroxide was gradually added thereto. The reaction mixture was stirred at room temperature for 3 hours, thereby a solution of pentafluorobenzenesulfonic acid tetramethylammonium salt was obtained. This solution was used for salt exchange of a sulfonium salt and an iodonium salt.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](O)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[N:7]=[C:2]([CH3:1])[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=1
Reactant: Cc1nc(O)ccc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A roundbottom flask was charged with a solution of 6-methyl-5-nitropyridin-2-ol (1.5 g, 9.74 mmol) in phosphorus oxychloride (5 ml). To the mixture was added phosphoryl pentachloride (2.0 g, 9.59 mmol). The resulting solution was allowed to react, with stirring, for three hours while the temperature was maintained at reflux. The mixture was poured into ice water and the solids that formed were collected by filtration to afford the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[O:25]1[CH:9]([CH2:8][CH:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:10]1
Reactant: C=CCC(c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: c1ccc(C(CC2CO2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 96.2 g. of 4,4-diphenyl-1-butene dissolved in 400 ml. of chloroform was added dropwise over one hour to a cold (0° C) suspension of 110.0 g. of m-chloroperbenzoic acid in 700 ml. of chloroform. The reaction mixture was warmed to about 25° C. and stirred for four hours. The reaction mixture was then washed with aqueous 2N sodium hydroxide solution, with water, and dried. Evaporation of the solvent under reduced pressure provided 158.3 g. of a yellow oil as the crude product. The oil was distilled to afford 1,2-epoxy-4,4-diphenyl-butane. B.P. 124°-126° C at 0.03 torr.
Reaction SMILES: [C:1](I)([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23]>>[C:1]([CH2:23][CH2:22][C:21]([O:25][CH2:26][CH3:27])=[O:24])([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: C=CC(=O)OCC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Product: CCOC(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
By causing 23 g. of C6F13I and 5 g. of ethyl acrylate to react under the conditions of Examples 3 to 7, there was obtained C6F13C2H4COOC2H5 and a dimer of the formula: ##STR6##
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:25])=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[CH2:23][OH:24])=[CH:15][CH:14]=2)[N:10]=1>[O-2].[O-2].[Mn+4]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:25])=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[CH:23]=[O:24])=[CH:17][CH:18]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1/C=C/c1ccc(/C=C/C=C/CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1oc(-c2ccco2)nc1/C=C/c1ccc(/C=C/C=C/C=O)cc1

Procedure:
(E,E,E)-5-[4-[2-[2-(2-Furyl)-5-methyl-4-oxazolyl]vinyl]phenyl]-2,4-pentadien-1-ol was oxidized with activated manganese dioxide in the same manner as in Reference Example 25 to yield (E,E,E)-5-[4-[2-[2-(2-furyl)-5- methyl-4-oxazolyl]vinyl]phenyl]-2,4-pentadien-1-al, which was then recrystallized from ethyl acetate to yield light brown prisms having a melting point of 179°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:31](=[O:33])[CH3:32])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1
Reactant: Cc1c(CCC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(O)cc12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)c(C)c(CCC(=O)O)n2Cc1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
Using the title compound of Example 23 as starting material, (1 g) was dissolved in CH2Cl2 (20 ml) at 0° C. and 1 ml pyridine added. 1.8 g acetic anhydride was added and the reaction let stir at 23° for 16 hours. The organic phase was washed with H2O (5×5 ml), evaporated and chromatographed.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[C:4]([O:21][CH3:22])=[C:5]([CH:11]=[C:12]([CH:14](O)CS(C)(=O)=O)[CH:13]=1)[N:6]([CH3:10])[C:7](=[O:9])[CH3:8].C[O-].[Na+].[NH:27]([CH2:34][CH2:35][C:36]#[N:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CS(C)=O>[NH:27]([CH:34]=[C:35]([C:36]#[N:37])[CH2:14][C:12]1[CH:13]=[C:3]([N:2]([CH3:23])[CH3:1])[C:4]([O:21][CH3:22])=[C:5]([CH:11]=1)[N:6]([CH3:10])[C:7](=[O:9])[CH3:8])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N#CCCNc1ccccc1
Reactant: COc1c(N(C)C)cc(C(O)CS(C)(=O)=O)cc1N(C)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(N(C)C)cc(CC(C#N)=CNc2ccccc2)cc1N(C)C(C)=O

Procedure:
A mixture of 10.6 g. of 3'-dimethylamino-5'-[1-hydroxy-2-(methylsulfonyl)-ethyl]-2'-methoxy-N-methylacetanilide, 1.8 g. of sodium methylate and 4.8 g. of β-anilinopropionitrile in 20 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 5 hours at 50° C. The mixture was poured into 250 ml. of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with benzene and recrystallization from ethyl acetate/petroleum ether, there was obtained the 5'-(3-anilino-2-cyanoallyl)-3'-dimethylamino-2'-methoxy-N-methylacetanilide, having a melting point of 176°-178° C.