Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Ba+2].[Cl:6][CH2:7][C:8]([OH:10])=[O:9].[CH3:11][CH2:12][CH2:13][CH2:14][CH:15]1[C:50](=[O:51])[O:49][CH:48]([CH:52]([CH:54]([OH:62])[CH2:55][CH2:56][CH2:57][NH:58][C:59]([NH2:61])=[NH:60])[CH3:53])[CH:47]([CH3:63])[CH:46]=[C:45]([CH3:64])[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]([OH:65])[CH2:39][CH:38]([OH:66])[CH2:37][CH:36]([OH:67])[CH2:35][CH:34]([OH:68])[CH2:33][CH:32]([OH:69])[CH:31]([O:70][C@H:71]2[O:75][C@H:74]([CH2:76][OH:77])[C@@H:73]([OH:78])[C@@H:72]2[OH:79])[CH:30]=[C:29]([CH3:80])[CH:28]([OH:81])[CH2:27][CH2:26][CH2:25][CH:24]([OH:82])[CH2:23][CH2:22][CH2:21][CH:20]([OH:83])[CH2:19][CH2:18][CH:17]([CH3:84])[CH:16]1[OH:85].S([O-])([O-])(=O)=O>CO.O>[CH3:11][CH2:12][CH2:13][CH2:14][CH:15]1[C:50](=[O:51])[O:49][CH:48]([CH:52]([CH:54]([OH:62])[CH2:55][CH2:56][CH2:57][NH:58][C:59]([NH2:61])=[NH:60])[CH3:53])[CH:47]([CH3:63])[CH:46]=[C:45]([CH3:64])[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]([OH:65])[CH2:39][CH:38]([OH:66])[CH2:37][CH:36]([OH:67])[CH2:35][CH:34]([OH:68])[CH2:33][CH:32]([OH:69])[CH:31]([O:70][C@H:71]2[O:75][C@H:74]([CH2:76][OH:77])[C@@H:73]([OH:78])[C@@H:72]2[OH:79])[CH:30]=[C:29]([CH3:80])[CH:28]([OH:81])[CH2:27][CH2:26][CH2:25][CH:24]([OH:82])[CH2:23][CH2:22][CH2:21][CH:20]([OH:83])[CH2:19][CH2:18][CH:17]([CH3:84])[CH:16]1[OH:85].[Cl:6][CH2:7][C:8]([O-:10])=[O:9]
Reactant: O=C(O)CCl
Agent: CCCCC1C(=O)OC(C(C)C(O)CCCNC(=N)N)C(C)/C=C(\C)CCCCC(O)CC(O)CC(O)CC(O)CC(O)C(O[C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)/C=C(\C)C(O)CCCC(O)CCCC(O)CCC(C)C1O
Agent: CCCCC1C(=O)OC(C(C)C(O)CCCNC(=N)N)C(C)C=C(C)CCCCC(O)CC(O)CC(O)CC(O)CC(O)C(O[C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)C=C(C)C(O)CCCC(O)CCCC(O)CCC(C)C1O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: O=C([O-])CCl
Reaction time: 0.17 h

Procedure:
0.088 g (0.446 millimoles) of barium carbonate and 0.21 g (2.23 millimoles) of monochloro acetic acid are dissolved in 10 ml of a 1:1 mixture of methanol and water under heating. The still hot solution is added to a suspension of 1.0 g (0.887 millimoles) of primycin sulfate and 70 ml of methanol. The reaction mixture is heated to boiling for 10 minutes under constant stirring, the precipitated barium sulfate is filtered through Celite. The filtrate is evaporated in vacuo. The solid residue is treated with ether. The white powdery solid is washed on the filter three times with 10 ml of ether saturated with water each and dried to constant weight. Thus 0.97 g of primycin monochloroacetate is obtained, yield 93.3%. Mp.: 176° C., /α/D25 =+22.0°.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([CH:11](Cl)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](C(C)(C)C)(C)C)[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH3:30][C@@H:31]1[CH2:36][NH:35][C@H:34]([CH3:37])[CH2:33][NH:32]1.N[C@@H](C(N[C@@H](C(O)=O)C)=O)C.O=C1NCCNC1=O.O.[F-].C([N+](CC)(CC)CC)C>C(#N)C>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([N:32]2[CH2:33][C@@H:34]([CH3:37])[NH:35][CH2:36][C@H:31]2[CH3:30])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:29]
Reactant: C[C@@H]1CN[C@H](C)CN1
Reactant: CCN(CC)C(=O)c1ccc(C(Cl)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Agent: CC[N+](CC)(CC)CC
Agent: C[C@@H](N)C(=O)N[C@H](C)C(=O)O
Agent: O=C1NCCNC1=O
Solvent: CC#N
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(O)c2)N2C[C@@H](C)NC[C@H]2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
The procedure described in Example 12 was followed with 11.62 g (27 mmol) of N,N-diethyl-4-(3-(tert-butyldimethylsilyloxy)-α-chlorobenzyl) benzamide, prepared as in Example 11, and 9.42 g (82 mmol) of (-)-(2R,5R)-2,5-dimethylpiperazine, prepared from D-Ala-D-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pa.) as described by Jung and Rohloff (J. Org. Chem. 50, 4909-13(1985)). The crude product was dissolved in 100 mL of acetonitrile and 8.07 g (40 mmol) of tetraethylammonium fluoride hydrate was added. The solution was stirred at room temperature overnight. The solvent was evaporated, and the residue was treated with 100 mL of aqueous 1N hydrochloric acid and extracted with 200 mL of diethyl ether. The aqueous layer was adjusted to pH 8 with aqueous 5M sodium hydroxide, and extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and evaporated to give 8.03 g (75%) of N,N-diethyl-4-(3-hydroxy-α-((2R, 5R)-2,5-dimethyl-1-piperazinyl)benzyl)-benzamide as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([F:14])[CH2:11][C@H:10]([NH:15]C(=O)OC(C)(C)C)[CH2:9]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])=[N:33][C:32]=1[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])=[N:33][C:32]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([F:14])[CH2:11][C@H:10]([NH2:15])[CH2:9]1)=[O:44]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](F)CN(c2ccncc2N)C1
Product: Nc1sc(-c2ccccc2F)nc1C(=O)Nc1cnccc1N1C[C@@H](N)C[C@@H](F)C1

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with tert-butyl (3S,5R)-1-(3-aminopyridin-4-yl)-5-fluoropiperidin-3-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid. Obtained the desired product as a white solid (50 mg). ESIMS m/z=431.1 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[S:5][CH:6]=[C:7]([C:9]([O:11]CC)=[O:10])[N:8]=2)[CH2:3][CH2:2]1.Cl>C1COCC1.CO.O>[CH:1]1([C:4]2[S:5][CH:6]=[C:7]([C:9]([OH:11])=[O:10])[N:8]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1csc(C2CC2)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1csc(C2CC2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of ethyl 2-cyclopropyl-thiazole-4-carboxylate (0.443 g, 2.249 mmol) and LiOH monohydrate (0.472 g, 11.243 mmol) was added a mixture of THF/MeOH/H2O (3:1:1, 50 mL). The reaction was stirred at RT for 24 h. The solution was acidified by addition of conc. HCl (0.1 mL) and the volatiles were removed. Remaining aqueous solution was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness. MS m/z: 169.9 (M+H) Calc'd. for C7H7NO2S-170.0.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12]Br.COCC1C=C(C(O)=O)C=CC=1C1C=CC=CC=1C.C1COCC1.[CH3:38][S-:39].[Na+]>CC#N>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][S:39][CH3:38]
Reactant: COC(=O)c1ccc(Br)c(CBr)c1
Reactant: C[S-]
Agent: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)c1ccc(Br)c(CSC)c1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of methyl 4-bromo-3-(bromomethyl)benzoate, which preparation is described above, under Intermediate 28, Step 1, (2 g; 6.49 mmol; 1 eq.) in CH3CN (10 mL) and THF (10 mL) was added sodium thiomethoxide (0.50 g; 7.14 mmol; 1.10 eq.) and the mixture was stirred at reflux for 1 hour and at RT overnight. After concentration under vacuum, the mixture was partitioned between EtOAc and water. The organic layer was washed with NaCl sat. solution, dried over magnesium sulfate, filtered off and dried under vacuum to give the title compound as a yellow oil (1.7 g, 94%). 1H NMR (CDCl3) δ 7.99 (d, J=2.3 Hz, 1H), 7.77 (dd, J=8.3, 2.1 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 3.92 (s, 3H), 3.83 (s, 2H), 2.06 (s, 3H). HPLC (Method A) Rt 4.31 min (Purity: 87.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:12]=2)[N:3]=1
Reactant: Cc1cccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)n1
Yield: 38.6 %

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (1.3 g, 3.26 mmol) and p-toluenesulfonic acid monohydrate (0.26 g, 1.36 mmol) in toluene (200 ml) was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture (1.56 g) was purified by chromatography on silica gel using ethyl acetate/acetone (98/2) to give pure 2-methyl-6-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine (0.48 g, 38%) as a white solid: mp (DSC) 205° C. Anal. Calc'd. for C17H14N3SO2F30.25H2O: C, 52.91; H, 3.79; N, 10.89; S, 8.31. Found: C, 52.67; H, 3.55; N, 10.64; S, 8.68.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C([O-])(=O)C.[NH4+:17].O>C(O)CO>[NH2:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1
Reactant: [NH4+]
Reactant: O=c1cc(O)c2ccccc2o1
Agent: CC(=O)[O-]
Solvent: O
Solvent: OCCO
Product: Nc1cc(=O)oc2ccccc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 99.4 %

Procedure:
97.2 g of 4-hydroxycoumarin and 69.3 g of ammonium acetate in 300 ml of ethylene glycol are heated to 70° C. for 3 hours, whilst stirring, and to 160° C. for 6 hours, the mixture is cooled to 60° C., 1 liter of water is added, whilst stirring, and the mixture is cooled to room temperature. The colourless crystalline precipitate is filtered off, washed with water and dried in vacuo at 60° C. 96 g of 4-aminocoumarin in an almost pure form are obtained
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)O1.I[C:24]1[C:29](=[O:30])[NH:28][CH:27]=[C:26]([C:31]([O:33][CH3:34])=[O:32])[CH:25]=1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:30]=[C:29]1[NH:28][CH:27]=[C:26]([C:31]([O:33][CH3:34])=[O:32])[CH:25]=[C:24]1[C:9]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][NH:13]2
Reactant: CC1(C)OB(c2cc(C(F)(F)F)cc3[nH]ncc23)OC1(C)C
Reactant: COC(=O)c1c[nH]c(=O)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COC(=O)c1c[nH]c(=O)c(-c2cc(C(F)(F)F)cc3[nH]ncc23)c1
Temperature: 140 °C
Yield: 15 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-indazole (43 mg, 0.138 mmol), methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate (38.4 mg, 0.138 mmol) and PdCl2(dppf) (5.04 mg, 6.89 μmol) in dioxane (2 mL) and aqueous saturated NaHCO3 solution (0.5 mL) was heated in a microwave reactor at 140° C. for 30 minutes. The reaction mixture was subsequently filtered and purified via preparative HPLC, eluting with a gradient of 20-90% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give the title compound as a white solid (7 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.19 (s, 1H), 8.09-8.14 (m, 2H), 7.94 (s, 1H), 7.62 (s, 1H), 3.82 (s, 3H); ESI-MS m/z [M+H]+ calc'd for C15H10F3N3O3, 338.1. found 338.2.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH2:19][CH3:20])=[C:16]([Cl:18])[N:17]=2)=[O:12])[C@H:6]([O:21][CH2:22][CH3:23])[CH2:5]1)(=[S:3])[NH2:2].Br[CH:25]([CH2:35][CH3:36])[C:26](=O)[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28]>>[Cl:18][C:16]1[N:17]=[C:13]([C:11]([NH:10][C@H:7]2[CH2:8][CH2:9][N:4]([C:1]3[S:3][C:25]([CH2:35][CH3:36])=[C:26]([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])[N:2]=3)[CH2:5][C@H:6]2[O:21][CH2:22][CH3:23])=[O:12])[NH:14][C:15]=1[CH2:19][CH3:20]
Reactant: CCCCOC(=O)C(=O)C(Br)CC
Reactant: CCO[C@@H]1CN(C(N)=S)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)sc1CC
Yield: 89 %

Procedure:
The same operation as in Example (22b) was performed using cis(±)-N-(1-carbamothioyl-3-ethoxypiperidin-4-yl)-4-chloro-5-ethyl-1H-imidazole-2-carboxamide obtained in Example (76b) (104 mg, 0.29 mmol) and butyl 3-bromo-2-oxopentanoate obtained by the method described in Example (110a) (113 mg, 0.45 mmol), to obtain 132.1 mg of the title compound (89%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:22]=[CH:21][NH:20][C:19]=1[CH:23]=O>N1CCCCC1.C(O)C>[CH3:17][C:18]1[N:22]=[CH:21][NH:20][C:19]=1[CH:23]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1nc[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1nc[nH]c1C=C1C(=O)Nc2cccc(-c3ccncc3)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 10.7 %

Procedure:
A mixture of 4-pyridin-4-yl-1,3-dihydroindol-2-one (50 mg, 0.24 mmol), 5-methyl-3H-imidazole-4-carbaldehyde (24.4 mg, 0.24 mmol) and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 2 days. The precipitate which formed was filtered. Crystals which formed in the filtrate were isolated, washed with ethanol and dried to give 7.8 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]#[N:7])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:8]=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:27][C:6]=1[NH2:7])=[O:17])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C#N)NC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(-c2ccccc2)sc1N
Temperature: 100 °C
Reaction time: 120 h

Procedure:
A solution of benzoylamino-cyano-acetic acid ethyl ester (400 mg, 1.7 mmol) in toluene (4 ml) was flushed with argon, and Lawesson's reagent (314 mg, 0.85 mmol) was added. The reaction mixture was stirred at 100° C. for 5 days. The solvent was evaporated, and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as yellow solid (147 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[OH:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](O)=[O:30]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]=2[OH:18])=[O:30])[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1Cc1ccccc1
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1Cc1ccccc1

Procedure:
(2S,4S)-1-Benzyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester was prepared from (2S,4S)-4-amino-1-benzyl-pyrrolidine-2-carboxylic acid methyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C24H25N2O4 [(M+H)+] 405.0, obsd. 405.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:17][CH2:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=O.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH:5]=[CH:4][C:3]=1[N:17]1[CH2:18][C:19]2[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:21]1=[O:23]
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(NCc2ccccc2C(=O)O)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C(=O)OC(C)(C)C)c1ccc(N2Cc3ccccc3C2=O)c(Br)c1
Temperature: 0 °C
Yield: 84.4 %

Procedure:
A mixture of 2-((2-bromo-4-(1-tert-butoxy-1-oxopropan-2-yl)phenylamino)methyl)benzoic acid (4.40 g, 10.1 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (2.13 g, 11.1 mmol) and 4-dimethylaminopyridine (0.617 g, 5.05 mmol) in methylene chloride (80 mL) was stirred at 0° C. and was allowed to warm to room temperature overnight. The mixture was then concentrated and the residue was purified by flash chromatography (silica, 4:1 hexanes/ethyl acetate) to afford tert-butyl 2-(3-bromo-4-(1-oxoisoindolin-2-yl)phenyl)propanoate (3.55 g, 85%) as white foam: 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J=7.6 Hz, 1H), 7.64-7.50 (m, 4H), 7.35 (d, J=1.0 Hz, 2H), 4.79 (s, 2H), 3.63 (q, J=7.2 Hz, 1H), 1.47 (d, J=7.2 Hz, 3H), 1.44 (s, 9H); ESI MS m/z 418 [(M+2)+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7](=[O:9])[CH3:8].[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C>[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:10]=[N+:11]=[N-:12])(=[O:9])[CH3:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCCCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCN=[N+]=[N-]
Temperature: 80 °C
Yield: 81 %

Procedure:
To a 500 mL flask was added 5.0 g (33 mmol, 1.0 eq) of 4-chlorobutylacetate and dissolved in 100 mL of DMF. Next 2.6 g (40 mmol, 1.2 eq) of sodium azide was added by a glass pipette. A water condenser was placed onto the flask and the reaction heated to 80° C. for 16 hr with stirring. The reaction was then cooled to room temperature and quenched with 300 mL of water to dissolve the sodium salts. The aqueous solution was extracted with diethyl ether 3×100 mL. The organic layers were combined and dried with MgSO4. The solution was filtered and concentrated under vacuum with no external heat, resulting in 4-azido-1-butylacetate (4.22), which was carried onto the next step without further purification; 1H NMR (CDCl3, 300 MHz): δ: 4.04 (t, J=6.0 Hz, 2H), 3.27 (t, J=6.2 Hz, 2H), 2.00 (s, 3H), 1.76-1.52 (m, 4H). 13C NMR (75 MHz, CDCl3) δ: 170.82, 63.55, 50.84, 25.73, 25.39, 20.73. 81% yield, clear oil.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+:22]>O>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[K+:22]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Reaction time: 2 h

Procedure:
In a 2-liter beaker equipped with a stirrer are placed 141 g of oleic acid (acid value: 198), 59 g of a 48% aqueous solution of caustic potash and 1406 g of water. A reaction is carried out for 2 hours at 30° C. with stirring to obtain an aqueous solution of potassium oleate having a pH value of 10.4 and containing 10.1% by weight of a solid matter.
Reaction SMILES: [NH:1]([C:13]([CH3:15])=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:16](O)[CH3:17]>Cl>[NH:1]([C:13]([CH3:15])=[O:14])[C@H:2]([C:10]([O:12][CH2:16][CH3:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(C)=O

Procedure:
To a solution of N-Ac-L-Phe (5.0 g, 24.1 mmol) in 120 ml of ethanol was added a few drops of concentrated HCl. The reaction mixture was refluxed overnight, then concentrated under reduced pressure. The residual solid was dissolved in ethyl acetate, washed twice with dilute NaHCO3, then once with water. The organic phase was dried over MgSO4, concentrated under reduced pressure, and dried under vacuum, to give N-Ac-Phe-OEt as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[N+:11]([O-])([OH:13])=[O:12]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Cl
Reactant: O=[N+]([O-])O
Product: Cc1cc(O)c([N+](=O)[O-])c(C)c1Cl
Temperature: 5 °C
Reaction time: 1 h

Procedure:
4-Chloro-3,5-dimethyl-phenol (20.0 g, 128 mmol) was dissolved in glacial acid (150 ml) and the solution was cooled to 5° C. Then nitric acid 65% (12.4 g, 128 mmol) was added dropwise while temperature was kept below 20° C. by external cooling. After the addition was complete stirring was continued for 1 hour at ambient temperature. The reaction mixture was poured into ice/water (1:1, 500 g) whereupon an orange solid precipitated. The solid was filtered off, washed with water and dried. Yield: 23.2 g (90.1%). 1H-NMR (DMSO-d6): δ=11.0 (s, 1H); 6.9 (s, 1H); 2.3 (s, 3H); 2.2 ppm (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[C:16]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[O:17][CH:18]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)(=[O:3])[CH3:2].ClC1C=C(C2N=C(CCC(O)=O)OC=2)C=C(C(F)(F)F)C=1>>[C:1]([C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[O:17][CH:18]=2)[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCc1nc(-c2cc(C(C)=O)cc(C(F)(F)F)c2)co1
Agent: O=C(O)CCc1nc(-c2cc(Cl)cc(C(F)(F)F)c2)co1
Product: CC(=O)c1cc(-c2coc(CCC(=O)O)n2)cc(C(F)(F)F)c1
Yield: 70 %

Procedure:
The title compound was prepared from methyl 3-(4-(3-acetyl-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 51) by a procedure similar to the one described for 3-(4-(3-chloro-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoic acid (Reference example 52) to provide 3-(4-(3-acetyl-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoic acid (0.081 g, 70%) as a white solid.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[O:37][N:36]=[C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:34]=3)[CH2:28][CH2:27]1)[C:18](O)([C:44]([O:46][CH3:47])=[O:45])[CH:17]2[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[O:37][N:36]=[C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:34]=3)[CH2:28][CH2:27]1)[C:18]([C:44]([O:46][CH3:47])=[O:45])=[C:17]2[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: COC(=O)C1(O)C(c2ccccc2)c2cc(Br)ccc2C(=O)N1CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.070 g) was added to a suspension of the compound prepared in Example 95 (0.56 g) in toluene (20 mL). The reaction mixture was heated at reflux under Dean-Stark conditions overnight. The reaction mixture was then cooled to room temperature and partitioned between dichloromethane and a saturated aqueous sodium bicarbonate solution. The combined organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=3:2) to obtain the title compound (0.35 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[C:25](Cl)=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:8][CH:7]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][OH:41])=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[C:25]([O:41][CH2:40][C:37]3[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CCc1ccc(Cn2c(-c3cccnc3Cl)nc3cc(F)c(F)cc32)cc1
Reactant: COc1ccc(CO)cc1
Product: COC(=O)CCc1ccc(Cn2c(-c3cccnc3OCc3ccc(OC)cc3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 3-{4-[2-(2-chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-phenyl}-propionic acid methyl ester and (4-methoxy-phenyl)-methanol (CAS Reg. No. 105-13-5). Colorless sticky solid (81%). MS (Turbo Spray): m/z=544.1 (M+H).