Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])(C)(C)C.C(O[C:25](=[O:41])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:29]=1)(C)(C)C>>[N:39]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[C:30]1[CH:29]=[C:28]([C:27]2[CH2:26][C:25](=[O:41])[NH:18][C:9]3[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ncccn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: O=C1CC(c2cccc(-c3ncccn3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (138 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K44) (164 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (75 mg).
Reaction SMILES: [OH:1][C@@H:2]([C:24]1[CH:33]=[CH:32][C:27]2[C:28](=[O:31])[O:29][CH2:30][C:26]=2[C:25]=1[CH3:34])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([C:13]2[CH:22]=[CH:21][C:16]3[C:17](=[O:20])[O:18][CH2:19][C:15]=3[C:14]=2[CH3:23])=[O:12])[CH2:6][CH2:5]1.[CH3:35][Li]>C1COCC1>[OH:12][C:11]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])([CH3:35])[CH2:10][N:7]1[CH2:6][CH2:5][N:4]([CH2:3][C@@H:2]([OH:1])[C:24]2[CH:33]=[CH:32][C:27]3[C:28](=[O:31])[O:29][CH2:30][C:26]=3[C:25]=2[CH3:34])[CH2:9][CH2:8]1
Reactant: Cc1c(C(=O)CN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Reactant: [Li]C
Solvent: C1CCOC1
Product: Cc1c([C@H](O)CN2CCN(CC(C)(O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Reaction time: 0.33 h

Procedure:
To a solution of 5-({4-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}acetyl)-4-methyl-2-benzofuran-1(3H)-one (50 mg, 0.108 mmol) in THF (2 mL) in a 25 mL flask was added methyl lithium (2 mg, 0.1 mmol) at 0° C. The reaction mixture was stirred for 20 min.; LC analysis indicated formation of the desired product. The solution was concentrated to dryness, dissolved in MeOH (3.5 mL), filtered and was then purified by mass-directed HPLC to give 5-(1-hydroxy-2-{4-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 481 [M+1]+.
Reaction SMILES: C(CCN[C:6](=[O:32])[C@@H:7]([NH:12][C:13]([N:15]1[C:19]2[CH2:20][CH2:21][O:22][CH2:23][C:18]=2[C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[N:16]1)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])#N.[NH:33]1[CH2:39][CH2:38][CH2:37][C@H:34]1[CH2:35][OH:36]>>[F:31][C:26]1[CH:25]=[C:24]([C:17]2[C:18]3[CH2:23][O:22][CH2:21][CH2:20][C:19]=3[N:15]([C:13]([NH:12][C@@H:7]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:6]([N:33]3[CH2:39][CH2:38][CH2:37][C@H:34]3[CH2:35][OH:36])=[O:32])=[O:14])[N:16]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCC#N
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)N1CCC[C@H]1CO

Procedure:
Compound 109 was prepared by the procedure described for the synthesis of compound 104 by replacing 2-cyanoethylamine with L-prolinol. LCMS (+ESI) m/z=477.3 [M+H]+. 1H NMR (CDCl3) δ 7.88 (d, J=9.7 Hz, 1H), 7.45-7.51 (m, 1H), 7.30-7.32 (m, 1H), 7.19-7.26 (m, 1H), 4.82 (s, 2H), 4.64 (d, J=9.8 Hz, 1H), 4.45 (br, 1H), 4.29-4.33 (m, 1H), 3.91-3.97 (m, 3H), 3.55-3.74 (m, 3H), 3.18 (br, 2H), 1.86-2.11 (m, 3H), 1.59-1.66 (m, 1H), 1.11 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[C:30]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)[CH:29]=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1ccc(O)cc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1OCC
Temperature: 90 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.19 g), ethyl 3-(2-ethoxy-4-hydroxyphenyl)propionate (0.76 g), anhydrous potassium carbonate (0.44 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.35 g, 82%) of ethyl 3-[2-ethoxy-4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 64-65° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[O:14][C:15](=[O:29])[CH:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C:18](=O)[CH2:17]4)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].Cl.[OH:31][NH2:32].C(N(CC)CC)C.[Cl-].[NH4+]>C(O)C>[OH:31][N:32]=[C:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[CH:16]([C:15](=[O:29])[O:14][C:13]3[C@H:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:10][CH2:11]4)[CH2:17]1
Reactant: NO
Reactant: CC(C)CCC[C@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)CC1C(=O)O3
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)CCC[C@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=NO)CC1C(=O)O3
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
Compound 1 (172 mg, 0.429 mmol) obtained in Example 1 was dissolved in ethanol (4.0 mL), and hydroxyamine hydrochloride (89.5 mg, 1.29 mmol) and triethylamine (178 μL, 1.29 mmol) were added thereto at room temperature, followed by stirring for 20 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography to obtain the title compound (160 mg, 90%) as a mixture of E-form and Z-form.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[CH:14]1([CH2:17]Br)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:14]1([CH2:17][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[C:6]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1nc([N+](=O)[O-])c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc([N+](=O)[O-])cn1CC1CC1

Procedure:
15 g (81 mmol) of ethyl 4-nitro-1H-imidazole-2-carboxylate are stirred together with 13.13 g (97.2 mmol) of cyclopropylmethyl bromide and 22.4 g (162 mmol) of potassium carbonate in 165 ml of DMF at 80° C. under argon for 1 h. After cooling, the reaction mixture is diluted with water and extracted four times with ethyl acetate. The combined organic phases are washed once with water and three times with saturated sodium chloride solution, dried with magnesium sulphate and evaporated in vacuo. The crystalline residue is further used directly for the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([Cl:38])=[C:33]([CH:37]=1)[C:34](O)=[O:35])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CCO>[CH3:18][O:17][C:11]1[CH:12]=[CH:13][C:14]([NH:16][C:34](=[O:35])[C:33]2[CH:37]=[C:29]([CH2:28][NH:27][C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH:30]=[CH:31][C:32]=2[Cl:38])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: COc1ccc(N)cc1C(=O)Nc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cc(CNC(=O)OC(C)(C)C)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1

Procedure:
Prepared analogously to Example 4c from N-(4-bromophenyl)-2-methoxy-5-amino-benzoic acid amide and 5-(tert.butoxycarbonylamino)methyl-2-chloro benzoic acid with TBTU and TEA. Yield: (85%). MS [m+H]+=588 (Br/Cl-isotope pattern); TLC: Rf=0.60 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: [Cl:1][C:2]1[C:3](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:5]([S:14]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH3:28])([CH3:27])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].Br[C:39]1[C:44]([C:45]#[N:46])=[CH:43][C:42]([C:47]([F:50])([F:49])[F:48])=[N:41][CH:40]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:13]=[C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([S:14]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH3:27])([CH3:28])[CH2:19][CH2:18]2)(=[O:15])=[O:16])=[CH:4][C:3]=1[C:39]1[C:44]([C:45]#[N:46])=[CH:43][C:42]([C:47]([F:49])([F:50])[F:48])=[N:41][CH:40]=1
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
Reactant: CC1(C)CCN(S(=O)(=O)c2cc(B3OC(C)(C)C(C)(C)O3)c(Cl)cc2OCCCCO)c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)CCN(S(=O)(=O)c2cc(-c3cnc(C(F)(F)F)cc3C#N)c(Cl)cc2OCCCCO)c2ccccc21
Temperature: 100 °C
Yield: 35.5 %

Procedure:
A mixture of 4-[5-Chloro-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butan-1-ol (270.0 mg, 0.49 mmol), 5-bromo-2-trifluoromethyl-isonicotinonitrile (112 mg, 0.45 mmol), Pd(Ph3P)4 (57 mg, 0.05 mmol) and Na2CO3 (286 mg, 2.7 mmol) in dioxane (4 mL) and water (0.4 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and then heated at 100° C. for 16 hrs. The mixture was then partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with brine (2×10 mL), dried over MgSO4, filtered and concentrated to give a material which was purified by TLC plates eluting with 30% acetone in hexanes to give 5-[2-chloro-5-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(4-hydroxy-butoxy)-phenyl]-2-trifluoromethyl-isonicotinonitrile 11-1 as a white solid (95 mg). MS: 594.2 (M+H)+; tR=2.94 min (method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([O:26]CC)=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([F:22])([F:23])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([OH:26])=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccc(F)c(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1

Procedure:
3.60 g (8.72 mmol) of the compound of Example 27A are provided in 50 ml of 1,4-dioxane, 50 ml (50 mmol) of a 1N solution of lithium hydroxide in water are added, and the mixture is heated under reflux for 1 h. The mixture is concentrated, the residue is diluted with water, a conc. aqueous hydrogen chloride solution is subsequently added until the pH is acidic, the mixture is extracted with ethyl acetate, and the organic phase is dried over magnesium sulfate, filtered and concentrated. 3.30 g (98% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:13]=2)[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1.[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30]>C(Cl)Cl>[F:10][CH:9]([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])=[CH:4][C:5]=1[C:12]1[NH:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:13]=1
Reactant: CC(C)C(=O)Cl
Reactant: NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Solvent: ClCCl
Product: CC(C)C(=O)NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 27.4 %

Procedure:
The title compound was prepared by following the procedure as described in Example-108 by using 3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (step-1 of Example-186, 0.50 g, 0.12 mmol), isobutyryl chloride (0.017 g, 0.15 mmol), TEA (0.042 g, 0.41 mmol) and DCM (10 mL) to afford 0.015 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.14-1.21 (m, 6H), 2.47 (m, 1H), 4.47 (s, 2H), 7.32-7.54 (m, 1H), 7.72 (d, J=8.7 Hz, 2H), 8.09 (br s, 1H), 8.18 (d, J=7.8 Hz, 2H), 8.70 (s, 1H); MS (m/z): 456.14 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:15]=[CH:16][N:17]=2)[C:5]([NH2:14])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]2[N:4]([N:15]=[CH:16][N:17]=2)[C:5]([NH:14][C:18](=[O:20])[CH3:19])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(-c2ccccc2)nc(N)n2ncnc12
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(-c2ccccc2)c(C)c2ncnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.6 Parts of 8-methyl-7-phenyl-1,2,4-triazolo[2,3-c]pyrimidin-5-amine (Example 1) is suspended in 50 parts by volume pyridine and 10 parts by volume acetic anhydride. The solution is stirred at room temperature for approximately 18 hours until a clear solution is formed. After approximately 21 hours turbidity develops and a solid gradually forms. After standing for approximately 40 hours most of the solvent is removed in vacuo. The residue is stirred in water, filtered, washed with water and dried. The product is recrystallized from methanol to give N-[8-methyl-7-phenyl-1,2,4-triazolo[2,3-c]pyrimidin-5-yl]acetamide having the formula: ##STR8##
Reaction SMILES: [C:1]([O:9][CH:10]([CH2:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:11][O:12][C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH:46]1[C:51]([Cl:52])=[CH:50][C:49](O)=[C:48]([O:54][C:55]2[CH:56]=[CH:57][C:58]([Cl:62])=[CH:59][C:60]=2[Cl:61])[CH:47]=1>C1(C)C=CC=CC=1>[C:5]([O:7][C:49]1[CH:50]=[C:51]([Cl:52])[CH:46]=[CH:47][C:48]=1[O:54][C:55]1[CH:56]=[CH:57][C:58]([Cl:62])=[CH:59][C:60]=1[Cl:61])(=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([O:9][CH:10]([CH2:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:11][O:12][C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:8]
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reactant: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OC(=O)CCCC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OC(=O)CCCC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reaction time: 20 h

Procedure:
2-Octanoyloxy-1-(octanoyloxymethyl)ethyl hydrogen glutarate (4.22 g.) was dissolved in dry toluene (40 ml.) and stirred with trifluoroacetic anhydride (5.2 ml.) for 2.5 hours. Triclosan (2.67 g.) was added and the mixture stirred for a further 20 hours. The solution obtained was washed successively with water (2×40 ml.), saturated sodium bicarbonate solution (2×40 ml.) and saturated brine (40 ml.). The organic phase was dried (MgSO4) and evaporated. The oil obtained was chromatographed on silica gel using methylene chloride as eluant to give 5-chloro-2-(2,4-dichlorophenoxy)phenyl 2-octanoyloxy-1-(octanoyloxymethyl)ethyl glutarate as an oil, having the same NMR and mass spectra as described for the ester in Example 1.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([PH:13](=[O:17])[O:14][CH2:15][CH3:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([CH:31]=[CH2:32])[CH:22]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([P:13]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:29])[CH3:30])=[C:23]([CH:31]=[CH2:32])[CH:22]=2)(=[O:17])[O:14][CH2:15][CH3:16])[CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:8]=1
Reactant: C=Cc1cc(Br)ccc1OC(C)C
Reactant: CCO[PH](=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=Cc1cc(P(=O)(OCC)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1OC(C)C
Temperature: 70 °C
Yield: 2.8 %

Procedure:
To a degassed solution of ethyl 3,5-bis(trifluoromethyl)-phenylphosphinate (3.33 g, 15.24 mmol) and 4-bromo-1-isopropoxy-2-vinylbenzene (3.33 mg, 13.8 mmol) in DMF (25 mL) were added the triethylamine (3.85 mL, 27.6 mmol) and tris(dibenzylideneacetone)dipalladium (2.53 g, 2.76 mmol). The mixture was heated in an oil bath at 70° C. overnight. The volatiles were removed in vacuo and the mixture was purified by column chromatography with 20 to 70% ethyl acetate in petroleum ether to afford compound BA3 (185 mg) as an oil in 2.8% yield.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([C:20]2[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:14]1([C:20]2[CH:21]=[CH:22][C:23]([C:24]([N:9]3[C:10](=[O:12])[CH2:11][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8]3=[O:13])=[O:25])=[CH:27][CH:28]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Solvent: c1ccncc1
Product: O=C1CN(c2ccccc2)C(=O)N1C(=O)c1ccc(-c2ccccc2)cc1
Yield: 9.4 %

Procedure:
In a similar manner to Example 8, 530 mg (3.00 mmol) of 1-phenyl-imidazolidin-2,4-dione were reacted with 650 mg (3.00 mmol) of 4-phenylbenzoyl chloride. After completion of the reaction, pyridine was distilled off under reduced pressure, and the resultant residue was subjected to extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and with saturated saline. The thus-washed organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off. The resultant residue was purified by column chromatography on silica gel (developing solvent: n-hexane/ethyl acetate) and subjected to crystallization from n-hexane/ethyl acetate to obtain 100 mg (yield: 9.9%) of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]=[N+:21]=[N-:22])[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:4][CH2:3]1.C([O:30][C:31](=[O:34])[C:32]#[CH:33])(C)(C)C.C(OCC)(=O)C>O1CCOCC1>[O:25]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:33]=[C:32]([C:31]([OH:34])=[O:30])[N:22]=[N:21]4)[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:6][CH2:7]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: C#CC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)c1cn(C[C@H]2CN(c3ccc(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1
Yield: 40.2 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one (6.9 g, 18.83 mmol) (Reference Example 2) was dissolved in dry 1,4-dioxane (15 ml), 2-propynoic acid t-butylester (4.75 g, 37.67 mmol) was added and the resulting mixture was refluxed for 12 hours under vigorous stirring. Ethyl acetate (30 ml) was added and the resulting precipitate was filtered, washed with ethyl acetate and dried as a white solid (5 g). This solid was suspended in dichloromethane (16 ml), followed by drop wise addition of trifluoroacetic acid (8 ml) and the resulting mixture was stirred over night. The solvent was removed under vacuum and the residue was purified by precipitation from dichloromethane to give the title product as an off-white solid (3.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]([F:25])([F:24])[F:23])=[N:10]2)=[CH:5][CH:4]=1.[ClH:26]>CO.[Pd]>[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]([F:25])([F:23])[F:24])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(C#N)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(CN)cc2)cc1
Reaction time: 5 h

Procedure:
A mixture of 4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]benzonitrile obtained by Example 56 (430 mg), Pd/C (100 mg) and 1N hydrochloric acid (1.3 ml) in methanol (43 ml) was stirred under Hydrogen atmosphere for 5 hrs.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]([O:12]C)=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:14](#[N:16])[CH3:15]>C1COCC1>[O:12]=[C:10]([CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:15][C:14]#[N:16]
Reactant: COC(=O)Cc1ccccc1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 26.1 %

Procedure:
To a suspension of 60% sodium hydride in mineral oil (1.00 g, 25.0 mmol) in THF (40 mL) at reflux is added a solution of methyl phenylacetate (2.50 g, 16.6 mmol) and anhydrous acetonitrile (1.74 mL, 33.3 mmol) in THF (40 mL), dropwise. The mixture is stirred at reflux for 6 h, then cooled to room temperature and stirred an additional 16 h. The reaction is quenched with H2O and is stirred for 10 min, after which the mixture is diluted with ethyl acetate and saturated aqueous NaHCO3 solution. The layers are separated and the aqueous layer is extracted with ethyl acetate. The organic layers are washed with brine and dried (Na2SO4). The solvent is removed in vacuo and the crude material is purified via flash column chromatography using a gradient elution of 0-40% ethyl acetate/heptane to afford the title compound as a yellow oil (690 mg, 26%). LCMS: 160.20 (M+H+).
Reaction SMILES: [CH:1]1([C:4]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:16]([CH:25]3[CH2:27][CH2:26]3)=[CH:15][N:14]=2)=[O:12])([CH3:9])[CH2:5][C:6]([OH:8])=O)[CH2:3][CH2:2]1.[Cl-].[NH4+:29]>>[NH2:29][C:6](=[O:8])[CH2:5][C:4]([NH:10][C:11]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:22])([F:23])[F:24])[C:16]([CH:25]2[CH2:26][CH2:27]2)=[CH:15][N:14]=1)=[O:12])([CH:1]1[CH2:2][CH2:3]1)[CH3:9]
Reactant: CC(CC(=O)O)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C1CC1
Reactant: [NH4+]
Agent: [Cl-]
Product: CC(CC(N)=O)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 3-cyclopropyl-3-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]butanoic acid (Example 229d) and ammonium chloride as starting materials and isolated (72 mg, 48%); MS (ESI, m/z): 386.6 (M+H+).