Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:24])[CH:3]=1.[CH3:25][C:26]1([CH3:32])[O:30][C:29](=[O:31])[N:28]=[CH:27]1>>[F:24][C:4]1[CH:3]=[C:2]([N:28]2[CH2:27][C:26]([CH3:32])([CH3:25])[O:30][C:29]2=[O:31])[CH:7]=[C:6]([F:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: CC1(C)C=NC(=O)O1
Reactant: Cc1ccc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)nc1
Product: Cc1ccc(N2CCN(C(=O)c3c(F)cc(N4CC(C)(C)OC4=O)cc3F)CC2)nc1
Yield: 47.7 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2,6-difluorophenyl)[4-(5-methylpyridin-2-yl)piperazin-1-yl]methanone (594 mg) described in Preparation Example 185 and 5,5-dimethyloxazolin-2-one (207 mg) described in Preparation Example 43, the title compound (308 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][C:18](B(O)O)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.C(N(CC)CC)C.C(COC)OC>C(OCC)(=O)C.O>[Cl:1][C:2]1[N:11]=[C:10]([C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[NH:13][CH:14]=[CH:15]3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1nc(-c2ccc3[nH]ccc3c2)c2ccccc2n1
Temperature: 80 °C
Yield: 65.8 %

Procedure:
To a round bottomed flask containing 2,4-dichloroquinazoline (800 mg, 4.02 mmol) was added indol-5-boronic acid (647 mg, 4.02 mmol), dichloro-((bis-diphenylphosphino)-ferrocenyl)-palladium (II) (complex with methylene chloride, 235 mg, 0.32 mmol), triethylamine (1.5 mL, 10 mmol), dimethoxyethane (20 mL), and water (0.5 mL). The reaction mixture was heated at 80° C. for 14 h, then cooled to rt and diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The material was purified by flash column chromatography to afford 2-chloro-4-(1H-indol-5-yl)quinazoline as a brown solid (740 mg, 66%).
Reaction SMILES: [Cl:1][C@H:2]1[CH2:6][N:5](C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[C@@H:4]2[C@@H:24]([OH:27])[CH2:25][O:26][C@H:3]12.Cl[C@H]1CN(C(OCC2C=CC=CC=2)=O)[C@@H]2[C@@H](O)CO[C@H]12.[H][H]>[Pd].C(O)C>[Cl:1][C@H:2]1[CH2:6][NH:5][C@@H:4]2[C@@H:24]([OH:27])[CH2:25][O:26][C@H:3]12
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1C[C@H](Cl)[C@H]2OC[C@H](O)[C@H]21
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(OCc1ccccc1)N1C[C@H](Cl)[C@H]2OC[C@H](O)[C@H]21
Solvent: CCO
Product: O[C@H]1CO[C@H]2[C@@H]1NC[C@@H]2Cl
Reaction time: 0.58 h

Procedure:
(3R,3aR,6S,6aS)-(9H-Fluoren-9-yl)methyl 6-chloro-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (70). Ethanol (8.5 mL) was added dropwise to a mixture of 10% palladium on charcoal (55 mg) and alcohol (68) (550 mg, 1.85 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 1 hour 35 minutes before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol (45 mL) then the solvents removed in vacuo from the filtrate. The residue was azeotroped with toluene (3×5 mL) to obtain (3R,3aR,6S,6aS)-6-chlorohexahydro-2H-furo[3,2-b]pyrrol-3-ol (69) which was used without further purification.
Reaction SMILES: [CH2:1]([N:7]([CH3:27])[C:8]([CH:10]1[CH2:14][CH:13]([OH:15])[CH2:12][CH:11]1[C:16]([NH:18][C:19]1([C:24]([OH:26])=[O:25])[CH2:21][CH:20]1[CH:22]=[CH2:23])=[O:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].Cl[C:31]1[C:40]2[C:35](=[CH:36][C:37](OC)=[CH:38][CH:39]=2)[N:34]=[C:33]([C:43]2[S:44][CH:45]=[C:46]([CH:48]([CH3:50])[CH3:49])[N:47]=2)[N:32]=1.Cl>C1COCC1.CCOC(C)=O>[CH2:1]([N:7]([CH3:27])[C:8]([CH:10]1[CH2:14][CH:13]([O:15][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[C:33]([C:43]3[S:44][CH:45]=[C:46]([CH:48]([CH3:50])[CH3:49])[N:47]=3)[N:32]=2)[CH2:12][CH:11]1[C:16]([NH:18][C:19]1([C:24]([OH:26])=[O:25])[CH2:21][CH:20]1[CH:22]=[CH2:23])=[O:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: COc1ccc2c(Cl)nc(-c3nc(C(C)C)cs3)nc2c1
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)O)CC1C=C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-c3nc(C(C)C)cs3)nc3ccccc23)CC1C(=O)NC1(C(=O)O)CC1C=C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
Compound 37 (26 mg, 70 μmol) was dissolved in THF (3 mL, dried with mol. siev.). To this solution was added NaH (60% in oil, 8.2 mg, 210 μmol) and the reaction was incubated for 10 min at ambient temperature. To the reaction mixture was then added compound 39 (17.6 mg, 61 μmol) followed by incubation at ambient temperature for 16 h. To the reaction was then added 0.1 M HCl (aq) and EtOAc, the phases separated and the aqueous phase extracted with another portion of EtOAc. The pooled organic phases were dried (MgSO4), filtered and concentrated in vacuo which gave a crude product which was further purified by flash-chromatography (Silica; DCM:MeOH) to afford the title compound (30 mg, 78%). LC/MS>95%, m/z (ESI+)=632 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.O>C1COCC1>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:1][CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCCn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
1-(Hydroxyethyl)imidazole (5.30 g; 47.3 mmol) was dissolved in anhydrous THF (50 mL) and cooled in an ice-bath. Sodium hydride (2.08 g of a 60 wt % dispersion in oil, 52.0 mmol) was added in portions over 10 min. The ice-bath was removed, and the mixture was stirred at room temperature for 20 min. A solution of 1-fluoro-4-nitrobenzene (5.0 mL, 47.2 mmol) in anhydrous THF (10 mL) was added over 5 min and the mixture stirred for a further 1.5 hr. Water (a few mL) was cautiously added and the mixture concentrated under reduced pressure. The residue was partitioned between EA (75 mL) and water (75 mL), and the phases separated. The aqueous phase was extracted twice with EA and the combined organic layers extracted three times with 1N hydrochloric acid. The pH of these acidic extracts was then adjusted to 7 with 5N aqueous sodium hydroxide and the resulting milky solution extracted three times with EA. The combined organic extracts were washed with water and brine, then dried over magnesium sulfate and concentrated under reduced pressure to give 1-(2-(4-nitrophenoxy)-ethyl)-1H-imidazole (5.46 g) as a brown oil. A solution of 1-(2-(4-nitrophenoxy)ethyl)-1H-imidazole (5.46 g; 2.34 mmol) in ethanol (60 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (0.40 g) at room temperature for 20 hr. The mixture was filtered through diatomaceous earth and then concentrated under reduced pressure to give 4-[2-(1H-imidazol-1-yl)ethoxy]benzenamine (4.56 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:18])=[C:4]2[O:13][C:12]([C:15]([OH:17])=[O:16])([CH3:14])[CH2:11][CH2:10][C:5]2=[C:6]([CH3:9])[C:7]=1[OH:8].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:8][C:7]1[C:2]([CH3:1])=[C:3]([CH3:18])[C:4]2[O:13][C:12]([C:15]([O:17][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:16])([CH3:14])[CH2:11][CH2:10][C:5]=2[C:6]=1[CH3:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(C(=O)OCc1ccccc1)O2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.7 %

Procedure:
To a solution of Trolox® (10 g, 39.1 mmol) at) at 0° C. in DMF (50 mL), was added sodium hydride (60% dispersion in oil, 3.5 g, 87.9 mmol). The reaction mixture was stirred at 0° C. for 15 minutes and then benzyl bromide (17.1 g, 99.9 mmol) was added drop wise. The reaction mixture was allowed to warm to room temperature and stirred for overnight. DMF was evaporated under high vacuum and then the residue was dissolved in ethyl acetate (200 mL) and washed with 1 N aqueous HCl (100 mL) and brine (100 mL) to give 10.1 g (58.7%) of an oil of the intermediate, benzyl (6-benzyloxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carboxylate. 1H NMR (CDCl3) δ1.57 (s, 3H), 1.82 (m, 1H), 2.02 (s, 3H), 2.08 (s, 3H), 2.15 (s, 3H), 2.44 (m, 3H), 4.61 (s, 2H), 5.00 (q, 2H), 7.00-7.45 (m, 10H). MS(ES) m/z 431.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[O:11][CH2:12][CH2:13][C:14](O)=[O:15])=[O:7])=[CH:4][C:3]=1[C:24]1[CH:25]=[N:26][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:29]=1[C:30]#[N:31].[C:36]([O:40][C:41](=[O:46])[NH:42][CH2:43][CH2:44][NH2:45])([CH3:39])([CH3:38])[CH3:37].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[C:36]([O:40][C:41](=[O:46])[NH:42][CH2:43][CH2:44][NH:45][C:14](=[O:15])[CH2:13][CH2:12][O:11][C:10]1[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=1[N:8]([C:6](=[O:7])[C:5]1[CH:22]=[CH:23][C:2]([Cl:1])=[C:3]([C:24]2[CH:25]=[N:26][C:27]([C:32]([F:34])([F:35])[F:33])=[CH:28][C:29]=2[C:30]#[N:31])[CH:4]=1)[CH3:21])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid 11-4 (50 mg, 0.10 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester (51.5 mg, 0.54 mmol) in DMF (500 μL), EDCI (22 mg, 0.12 mmol), HOBt (16 mg, 0.12 mmol) and DIPEA (34 μl, 0.19 mmol) were added. The mixture was stirred for 48 hrs at rt, diluted with MeOH (500 μL) and purified by prep HPLC to afford {2-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionylamino]-ethyl}-carbamic acid tert-butyl ester. After treatment with 50% TFA in DCM (1 mL) for 2 hrs, followed by concentration in vacuo, N-{2-[2-(2-amino-ethylcarbamoyl)-ethoxy]-phenyl}-4-chloro-3-(4-cyano-trifluoromethyl-pyridin-3-yl)-N-methyl-benzamide 53-1 was obtained. MS [M+H]+546.1; tR=5.66 min (method 2).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]([C:22]([OH:24])=[O:23])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:25][CH:26]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:27][C@H:28]([CH3:40])[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:25][CH:26]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:27][C@H:28]([CH3:40])[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([O:23][C:22]([C:12]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][CH:15]=[C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:11]=2)=[O:24])=[CH:37][CH:38]=1
Reactant: CCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: CCCCC(Cl)C[C@H](C)CCCOc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)Oc2ccc(OCCC[C@@H](C)CC(Cl)CCCC)cc2)c1

Procedure:
0.65 g of 4-n-octoxybiphenylcarboxylic acid, 0.60 g of (R)-4-(6'-chloro-4'-methyldecyloxy)phenol, 0.04 g of N,N'-dicyclohexyl carbodiimide and 20 ml of dichloromethane were stirred for 3 hours at room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]C1C=CC=C(F)C=1.C1C(C(CBr)=O)=CC=C(F)C=1.C1C(C(CBr)=O)=CC=C(Br)C=1.[Mn]([O-])(=O)(=O)=O.[K+]>>[Br:1][C:2]1[CH:10]=[C:9]([Br:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1Br
Reactant: Fc1cccc(Br)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=C(CBr)c1ccc(Br)cc1
Agent: O=C(CBr)c1ccc(F)cc1
Product: O=C(O)c1ccc(Br)cc1Br

Procedure:
Some of the compounds of the general formula II are known and may be prepared by known methods. For example, 2-bromo-4-fluorobenzoic acid may be obtained from 1-bromo-3-fluorobenzene by acetylation and oxidation of the 2-bromo-4-fluoroacetophenone which is produced (Recl. Trav. Chim. Pays-Bas, 83 p. 1142, 1146 (1964)). The oxidation of 2,4-dibromoacetophenone using potassium permanganate to give 2,4-dibromobenzoic acid is described in J. Karnatak Univ. 1 p. 36 (1956). According to J. Chem. Soc. 85, 1267 ff. (1904), 5-chloro-2-bromobenzoic acid may be obtained by nitric acid oxidation of 5-chloro-2-bromotoluene.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([O:44][CH2:45][C@H:46](O)[CH3:47])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=1)[C:10]([O:12][C@H:46]([CH3:47])[CH2:45][O:44][C:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:43])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O
Reactant: C[C@@H](O)COC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@H](COC(=O)c1ccccc1)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
To a solution of (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoic acid (15.9 g, 33.3 mmol), (2R)-2-hydroxypropyl benzoate (5.0 g, 27.7 mmol), and 4-(dimethylamino)pyridine (340 mg) in 250 mL of anhydrous dichloromethane, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (8.0 g, 41.6 mmol) was slowly added. The resulting mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with dichloromethane and washed with 0.5N HCl twice, followed by the addition of brine. The organic layer was separated, dried through a MgSO4 pad and concentrated under reduced pressure. Chromatography (silica gel, 1:5 then 1:4 ethyl acetate/hexane) of the residue followed by crystallization from 1:5 ethyl acetate/hexane afforded 8.0 g (45%) of the title compound.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Ca+2:26].[OH-]>C(O)(=O)C>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Ca+2:26].[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Reaction time: 0.5 h

Procedure:
139.9 g of behenic acid and 19.0 g of calcium hydroxide were initially introduced and mixed with stirring at 60° to 65° C. After addition of 0.8 g of acetic acid (0.5%, based on the mixture as a whole), the temperature rose to 85° C. The total stirring time was 30 minutes; a dust-like powder was present after only 2 minutes. The reaction was carried out under a slight vacuum as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12](=[O:18])[CH2:13][C:14](=[O:17])[CH2:15][CH3:16].[CH:19](OCC)(OCC)[O:20][CH2:21][CH3:22].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12](=[O:18])[C:13](=[CH:19][O:20][CH2:21][CH3:22])[C:14](=[O:17])[CH2:15][CH3:16]
Reactant: CCOC(OCC)OCC
Reactant: CCC(=O)CC(=O)c1ccc(S(C)(=O)=O)cc1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)CC)C(=O)c1ccc(S(C)(=O)=O)cc1Cl
Yield: 85.9 %

Procedure:
A mixture of 1-[2-chloro-4-(methylsulphonyl)phenyl]pentan-1,3-dione (7.0 g), triethyl orthoformate (7.2 g) and acetic anhydride was stirred and heated at reflux for 4 hours. The mixture was cooled and evaporated to dryness. Toluene was added to the residue and then re-evaporated to give 1-[2-chloro-4-(methylsulphonyl)phenyl]-2-ethoxymethylenepentan-1,3-dione (7.18 g) as a sticky orange solid which was not purified further.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[O:8])=[CH:5][CH:4]=1)#[N:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:61]([O:68][C:69](=[O:77])[CH2:70][CH:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C(Cl)Cl>[CH2:61]([O:68][C:69](=[O:77])[CH2:70][CH:71]1[CH2:72][CH2:73][N:74]([C:12](=[O:13])[C:11]([CH3:15])([CH3:16])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:75][CH2:76]1)[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: O=C(CC1CCNCC1)OCc1ccccc1
Reactant: CC(C)(C(=O)O)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
N-4-Cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanine (0.5 g, 1.55 mmol) was dissolved in methylene chloride (30 ml). To the resulting solution, BOP reagent (0.89 g, 4.03 mmol) and diisopropylethyl-amine (DIEA) (1.67 ml, 9.3 mmol) were added under cooling with ice and the mixture was stirred for 30 minutes. To the reaction mixture was added 4-piperidineacetic acid benzyl ester (1.08 g, 4.65 mmol) and the resulting mixture was stirred overnight. After the solvent was distilled off, the residue was dissolved in ethyl acetate, washed sequentially with a 5% aqueous solution of citric acid, a 5% aqueous solution of sodium bicarbonate and a saturated aqueous solution of NaCl 3 times each and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was applied to a silica gel column (2.2×20 cm) and eluted with a mixed solution (hexane:ethyl acetate=3:1). The desired fractions were collected and the solvents were distilled off to yield an oil of N-4-cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid benzyl ester (0.58 g, 69.6%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3].[C:10]([OH:13])(=[S:12])[CH3:11]>>[C:10]([S:12][CH:4]([CH3:5])[CH:2]([CH3:3])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:13])[CH3:11]
Reactant: CC(O)=S
Reactant: C/C=C(\C)C(=O)OCC
Product: CCOC(=O)C(C)C(C)SC(C)=O

Procedure:
A mixture of 3.20 g (0.025 mol) of ethyl tiglate and 4.76 g (0.0625 mol) of thioacetic acid was prepared and allowed to react under nitrogen atmosphere at 85° C. for 24 hours. The results showed that the conversion rate of ethyl tiglate was 35.3%, and that the selectivity for the objective compound was 91.6%.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH:29]2[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC2CCOCC2)=O)CC1)#N>>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:24]([F:27])([F:25])[F:26])(=[O:15])=[O:16])[CH2:11][C@@H:10]2[O:28][CH:29]2[CH2:30][CH2:31][S:32](=[O:36])(=[O:35])[CH2:33][CH2:34]2)=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCS(=O)(=O)CC2)CC1
Agent: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCOCC2)CC1
Product: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@@H]2OC2CCS(=O)(=O)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 175 using (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-[(tetrahydro-1,1-dioxo-2H-thiopyran-4-yl)oxy]-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 181) instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-(tetrahydro-pyran-4-yloxy)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 533.1 (M−H)−.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:30][Mg]Br.Cl>O1CCCC1.CCOCC>[CH2:1]([O:17][CH2:18][CH:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:20]([OH:21])[CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(C=O)OCc1ccccc1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOCC(OCc1ccccc1)C(C)O
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a solution of 10 g of 3-(hexadecyloxy)-2-(phenylmethoxy)-propanal in 120 ml of dry tetrahydrofuran, under argon, at 5° C., was added dropwise 16.4 ml of 3M methyl magnesium bromide in ether at a rate to maintain the temperature below 8° C. The mixture was stirred at 5° C. for 15 minutes, then at room temperature for 3 hours, recooled to 5° C. and 50 ml of 1N hydrochloric acid was added dropwise at a rate to maintain the temperature below 10° C. The organic phase was separated and the aqueous phase extracted with ether. The ether extract was combined with the organic phase, washed with saturated aqueous sodium bicarbonate, then saturated brine, dried and taken to dryness. The residue was dissolved in petroleum ether, washed with saline, dried and taken to dryness. The residue was purified by HPLC using ether:hexane (1:5), giving 6.16 g of the desired compound as a pale yellow oil.