Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=C[CH:2]=1.CC(O)C.C([Sn](CC=C)(CC=C)CC=C)C=C.[Cl:40][CH2:41][CH2:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)=[O:44]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(Cl)Cl>[Cl:40][CH2:41][CH2:42][C:43]([C:45]1[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=1)([OH:44])[CH2:6][CH:1]=[CH2:2]
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Agent: [Ti+4]
Agent: C=CC[Sn](CC=C)(CC=C)CC=C
Agent: CC(C)[O-]
Solvent: CC(C)O
Solvent: ClCCl
Product: C=CCC(O)(CCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 1,1′-bi-2-naphthol (0.2280 g, 0.80 mmol, 0.26 equiv), CH2Cl2 (5 mL) and titanium(IV) isopropoxide (0.2243 g, 0.79 mmol, 0.26 equiv) were added 2-propanol (3.1620 g, 52.6 mmol, 17 equiv), tetraallylstannane (1.2538 g, 4.43 mmol, 1.43 equiv), and 3-chloro-1-(4-fluorophenyl)propan-1-one (0.5760 g, 3.09 mmol, 1.0 equiv) successively. The reaction mixture was stirred at rt under nitrogen for 22 h. The reaction was quenched with satd aq NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol as an oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:15]=[CH:16]/[C:17]2[N:18]=[C:19]3[N:23]([C:24]=2[C:25](O)=[O:26])[CH:22]=[CH:21][S:20]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:28][C:29]([F:37])([F:36])[C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:15]=[CH:16]/[C:17]2[N:18]=[C:19]3[N:23]([C:24]=2[C:25]([NH:35][C:32]2[S:33][CH:34]=[C:30]([C:29]([F:37])([F:36])[F:28])[N:31]=2)=[O:26])[CH:22]=[CH:21][S:20]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OC1CCCC1
Reactant: Nc1nc(C(F)(F)F)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(F)(F)F)cs2)c1OC1CCCC1

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 4 (200 mg, 0.520 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (105 mg, 0.624 mmol) in the presence of EDCI hydrochloride (200 mg, 1.040 mmol) and DMAP (159 mg, 1.300 mmol) in a mixture of DCM and DMF (4:1, 5 mL) to give 86 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.52-1.62 (m, 4H), 1.76-1.79 (m, 4H), 3.81 (s, 3H), 4.85 (br s, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.10 (t, J=8.1 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.43-7.49 (m, 2H), 7.82 (d, J=16.2 Hz, 1H), 8.06-8.10 (m, 2H), 12.99 (br s, 1H); ESI-MS (m/z) 535.11 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#N)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[OH-].[K+].[CH2:16](I)C.O>C(O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:11][CH2:12][CH3:16])=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
2-Nitro-4-thiocyanatoaniline (17.55 g.; prepared as hereinbefore described in Example 6) was added portionwise to a stirred solution of potassium hydroxide (13.4 g.) in ethanol (210 ml.), keeping the temperature below 20° C. After 5 minutes, ethyl iodide (14.4 g.) was added during five minutes. The stirring was continued for a further hour and the mixture was allowed to stand overnight. The mixture was then poured into water (1100 ml.) and extracted with chloroform (3× 300 ml.). The chloroform layers were combined, washed with water (500 ml.), dried over magnesium sulphate, and evaporated to give 1-amino-4-ethylthio-2-nitrobenzene (17.0 g.), in the form of a red oil.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=O)=[CH:22][N:21]=2)=[CH:4][CH:3]=1.[CH3:31][NH2:32].CO>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:32][CH3:31])=[O:28])=[CH:22][N:21]=2)=[CH:29][CH:30]=1
Reactant: CN
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(-c1ccc(C(=O)O)cn1)n2Cc1ccc(F)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)nc1
Temperature: 22.5 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1-(4-fluorobenzyl)-2-(5-carboxypyridin-2-yl)-5-methanesulfonylindole (20 mg), N,N′-carbonyldiimidazole (10 mg) and tetrahydrofuran (1 ml) was stirred at 15 to 30° C. for 10 minutes under nitrogen atmosphere, followed by addition of a 40% methylamine/methanol solution (0.1 ml), and the mixture was further stirred at 15 to 30° C. for 10 minutes. The reaction solution was then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:5) to obtain 13 mg of the desired product.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.ClC(OCC)=O.Cl.Cl.[CH2:36]([NH:43][NH2:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH2:36]([NH:43][NH:44][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: NNCc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NNCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 7.0 g linoleic acid in 250 ml methylenechloride cooled to -20° is added first 2.5 g triethylamine and then dropwise 2.7 g ethyl chloroformate. The reaction mixture is allowed gradually to come to room temperature and stirred for 2 hours. There is then added 5.0 g triethylamine followed by 4.9 g benzylhydrazine dihydrochloride and the reaction mixture then stirred for 16 hours. Thereafter the reaction mixture is extracted five times with portions of 2 N hydrochloric acid, then once with 2 N aqueous sodium hydroxide solution and washed extensively with saturated aqueous sodium chloride. The organic phase is then dried with anh. sodium sulphate, filtered and the filtrate evaporated i.v. to dryness. The residue is then chromatographed over silica gel, with chloroform as the eluent. The desired fractions* are collected, and evaporated i.v. to dryness to yield the title product as a viscous oil.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>C1COCC1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:2]([CH3:1])[S:3]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)(=[O:5])=[O:4])=[CH:13][CH:14]=2)([OH:23])[C:19]([F:21])([F:22])[F:20])=[CH:27][CH:26]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CN(c1ccc(C(=O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: CN(c1ccc(C(O)(c2ccc(Cl)cc2)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a solution of 0.2 g of N-methyl-N-(4-trifluoroacetyl-phenyl)-benzenesulfonamide in 10 mL of THF were added 0.7 mL of a 1M solution 4-chlorophenyl magnesium bromide at −78° C. The resulting mixture was stirred at −78° C. for 4 hr. After this time, the reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 7:1) to give the title compound. 1H-NMR (CDCl3) δ 2.96 (br s, 1H), 3.17 (s, 3H), 7.10–7.59 (m, 13H). Mass Spectrum (CI+) m/e=456 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[N:10]=[C:11](Cl)[NH:12][C:13](=[O:14])[C:8]=2[CH:7]=[CH:6]1)[CH2:2][CH:3]=[CH2:4].C(=O)([O-])[O-].[Na+].[Na+].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>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.C(O)C>[CH2:1]([N:5]1[C:9]2[N:10]=[C:11]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=3)[NH:12][C:13](=[O:14])[C:8]=2[CH:7]=[CH:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C=CCCn1ccc2c(=O)[nH]c(Cl)nc21
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: CCO
Product: C=CCCn1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)nc21
Temperature: 150 °C
Yield: 69 %

Procedure:
A microwave reaction vial was charged with 7-but-3-enyl-2-chloro-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (Intermediate B) (96.1 mg, 430 μmol,), ethanol (1.6 mL), a 2M aqueous sodium carbonate solution (645 μL, 1.29 mmol), 4-(trifluoromethyl)phenylboronic acid (98.2 mg, 517 μmol), and tetrakis(triphenylphosphine)palladium(0) (27.2 mg, 23.5 μmol). The reaction was heated in a microwave at 150° C. for 68 min. The reaction was filtered through a pad of Celite®, rinsing with ethanol. The filtrate was concentrated in vacuo onto Celite®. Flash chromatography (12 g silica gel column, 10-30% ethyl acetate/hexanes) afforded 7-but-3-enyl-2-(4-trifluoromethyl-phenyl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (98.9 mg, 69.1%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.59 (q, J=6.66 Hz, 2H) 4.29 (t, J=6.88 Hz, 2H) 4.84-5.21 (m, 2H) 5.58-5.95 (m, 1H) 6.52 (d, J=3.20 Hz, 1H) 7.25 (d, J=3.20 Hz, 1H) 7.90 (d, J=8.29 Hz, 2H) 8.34 (d, J=7.91 Hz, 2H) 12.32 (s, 1H). LC-MS calcd. for C17H15F3N3O [(M+H)+] 334, obsd. 334.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=1.[NH2:18][C:19]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:23][C:22]([Cl:32])=[CH:21][N:20]=1.O>CS(C)=O>[Cl:32][C:22]1[CH:23]=[C:24]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:8]3[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:29][CH:30]=2)[C:19]([NH2:18])=[N:20][CH:21]=1
Reactant: Fc1ncccc1C(F)(F)F
Reactant: Nc1ncc(Cl)cc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncc(Cl)cc1-c1ccc(Oc2ncccc2C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
A mixture of potassium carbonate (376 mg), 2-fluoro-3-(trifluoromethyl)pyridine (269 mg) and 4-(2-amino-5-chloropyridin-3-yl)phenol (300 mg) in DMSO (10 mL) was stirred at 120° C. for 3 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (470 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:57][C:58]1[NH:59][C:60]2[CH:66]=[CH:65][CH:64]=[CH:63][C:61]=2[N:62]=1>C(Cl)Cl>[NH:59]1[C:60]2[CH:66]=[CH:65][CH:64]=[CH:63][C:61]=2[N:62]=[C:58]1[NH:57][C:14](=[O:15])[CH:13]([C:5]1[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:3]([C:1]#[N:2])[CH:4]=1)[CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3[nH]2)cc1C#N
Yield: 95 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 26, 100 mg, 0.311 mmol), triethylamine (0.13 mL, 0.933 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (206 mg, 0.467 mmol), and 2-aminobenzimidazole (62 mg, 0.467 mmol) in methylene chloride (3 mL) was stirred at 25° C. for 3 h. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40S, Silica, 1/3 hexanes/ethyl acetate) to afford N-(1H-benzimidazol-2-yl)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (129 mg, 95%) as a yellow solid: mp 148-152° C.; EI-HRMS m/e calcd for C23H24N4O3S (M+) 436.1569, found 436.1573.
Reaction SMILES: C([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])C.COC([N:37]([C:52]1[C:61](C(OC)=O)=[C:60]2[C:55](C3CC3C[O:59]2)=CC=1)S(C1C=CC(F)=CC=1/C=C\CO)(=O)=O)=O.O[C@H]1CCNC1>>[OH:59][C@H:60]1[CH2:61][CH2:52][N:37]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[S:14]([NH:17][C:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]3[C:21]([CH:22]4[CH2:32][CH:23]4[CH2:24][O:25]3)=[CH:20][CH:19]=2)(=[O:15])=[O:16])[CH2:55]1
Reactant: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCC1CC21
Agent: O[C@H]1CCNC1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CNN2CC[C@H](O)C2)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 63, starting from methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzene-sulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 64) and (S)-3-hydroxypyrrolidine.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[N:16]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[C:22]([CH3:29])[N:23]=[CH:24]2)=[C:17]=[O:18].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[CH3:29][C:22]1[N:23]=[CH:24][C:25]2[C:20]([CH:21]=1)=[C:19]([NH:16][C:17]([NH:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:15][CH:14]=1)=[O:18])[CH:28]=[CH:27][CH:26]=2
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: CC1CCN(c2ccc(CN)cc2)CC1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCC(C)CC4)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-(4-methyl-1-piperidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.66 (s, 1H), 8.74 (s, 1H), 8.59 (d, 1H, J=8.7 Hz), 8.01 (d, 1H, J=8.7 Hz), 7.82 (m, 2H), 7.65 (m, 2H), 7.48 (m, 2H), 4.40 (d, 2H, J=6Hz), 3.54 (m, 4H), 2.78 (s, 3H), 1.90-1.50 (m, 5H), 0.98 (d, 3H, J=6 Hz); MS (ESI) 389 (M+H)+; Anal. Calcd for C24H28N4O.2.6HCl: C, 59.64; H, 6.38; N, 11.59. Found: C, 59.31; H, 6.39; N, 11.19.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:9]=2)[N:4]([S:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27](F)[CH:26]=2)(=[O:24])=[O:23])[CH2:3]1.[CH2:35]([OH:37])[CH3:36].[H-].[Na+].O>CN(C)C=O>[CH3:34][C:2]1([CH3:1])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:9]=2)[N:4]([S:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([O:37][CH2:35][CH3:36])[CH:26]=2)(=[O:24])=[O:23])[CH2:3]1
Reactant: CCO
Reactant: CC1(C)Cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N(S(=O)(=O)c2ccc(C#N)c(F)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(S(=O)(=O)N2CC(C)(C)Cc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)ccc1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
165 mg 4-[3,3-Dimethyl-6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinoline-1-sulfonyl]-2-fluoro-benzonitrile and 30 ml ethanol were dissolved in 3 ml dimethylformamide. Then 10 mg sodium hydride were added and the reaction mixture stirred at room temperature for 4 hours. The mixture was then poured into 20 ml water and extracted five times with portions of 20 ml ethyl acetate. The combined organic extracts were dried over MgSO4 then evaporated in vacuo and the residue purified by chromatography on silica gel to obtain 40 mg 4-[3,3-Dimethyl-6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinoline-1-sulfonyl]-2-ethoxy-benzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[OH:25])[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6].Cl[S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28].[K+].[Br-]>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:22]=[CH:23][C:24]=1[O:25][S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: O=C(NCCCCCCCCc1ccccc1)c1ccc(O)c(Br)c1
Agent: [Br-]
Agent: [K+]
Product: O=C(NCCCCCCCCc1ccccc1)c1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(Br)c1

Procedure:
The title compound was prepared as a white solid (0.388 g, 40%) from 3-bromo-4-hydroxy-N-(8-phenyloctyl)benzamide and 4-chlorosulfonyl-2-hydroxy-benzoic acid using a procedure similar to step 3 of Example 179. 1H NMR (DMSO-d6) δ8.57 (bt, 1H); 8.50 (d, 1H); 7.99 (dd, 1H); 7.86 (dd, 1H); 7.38-7.32 (m, 3H); 7.26-7.10 (m, 5H); 3.50 (bs, 2H); 3.20 (dd, 2H); 2.53 (t, 2H); 1.50 (m, 4H); 1.28 (m, 8H); IR (KBr) 3480, 3350, 2950, 2850, 1900, 1690, 1630, 1600, 1580, 1540, 1480, 1450, 1360, 1285, 1250, 1205, 1180, 1110, 1080, 1040, 930, 860 cm−1; mass spectrum [(+)APCI], r/z 604 (M+H)+; Anal. Calcd. for C28H30BrNO7S: C, 55.63; H, 5.00; N, 2.32, Found: C, 54.33; H, 5.11; N, 1.95.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:22]([CH2:32][CH2:33][CH3:34])=[N:21]2)=[CH:17][CH:16]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:22]([CH2:32][CH2:33][CH3:34])=[N:21]2)=[CH:17][CH:16]=1
Reactant: CCCc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-propyl-1H-pyrazol-4-yl]propionate (610 mg), 1N aqueous sodium hydroxide solution (2.6 ml), ethanol (3 ml), and tetrahydrofuran (3 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The crystals obtained were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-propyl-1H-pyrazol-4-yl]propionic acid (480 mg, yield: 80%). This was recrystallized from ethyl acetate-hexane. Melting point: 153–154° C.
Reaction SMILES: S.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=3)[O:12][C:11]2=[O:28])=[CH:6][CH:5]=1)#[N:3].[N:29]1C=CC=CC=1>C(N(CC)CC)C>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=3)[O:12][C:11]2=[O:28])=[CH:8][CH:9]=1)(=[NH:29])[NH2:3]
Reactant: COC(=O)Cc1ccc(OCC2CN(c3ccc(C#N)cc3)C(=O)O2)cc1
Reactant: c1ccncc1
Agent: S
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(OCC2CN(c3ccc(C(=N)N)cc3)C(=O)O2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
H2S gas is passed, at -10°, into a solution of 1.2 g of 3-p-cyanophenyl-5-(p-methoxycarbonylmethylphenoxymethyl)oxazolidin-2-one (obtainable in accordance with Example 1) in 50 ml of pyridine and 7 ml of triethylamine. The mixture is subsequently stirred at room temperature for 14 h and concentrated by evaporation; the residue is dissolved in 50 ml of acetone and treated with 9 ml of methyl iodide. After this mixture has been stirred for a further 6 h, it is filtered and the residue is washed with 5 ml of acetone and dissolved in 30 ml of methanol; 4.6 g of ammonium acetate are added to this solution, which is stirred at room temperature for 24 h. Following the customary working-up, 3-p-amidinophenyl-5-(p-methoxycarbonylmethylphenoxymethyl)oxazolidin-2-one (semihydriodide) is obtained, M.p. 151-152°.
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.O[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]=[C:17]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH:16]=1.[O:39]1[CH2:43][CH2:42][NH:41][C:40]1=[O:44].[H-].[Na+]>C(Cl)Cl>[O:44]=[C:40]1[N:41]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[N:18]=[C:17]([O:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:30][CH2:31]3)[CH:16]=2)[CH2:42][CH2:43][O:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(CO)cc(C(F)(F)F)n2)CC1
Reactant: O=C1NCCO1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(CN3CCOC3=O)cc(C(F)(F)F)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (220 μL, 1.6 mmol) and then methanesulfonyl chloride (82 μL, 1.1 mmol) were added to a solution of tert-butyl 4-{[4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.20 g, 0.53 mmol, from Step 2) in methylene chloride (2 mL) at 0° C. After stirring at this temperature for 30 minutes, the reaction mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude mesylate intermediate was dissolved in N,N-dimethylformamide (2.0 mL), and oxazolidin-2-one (230 mg, 2.6 mmol) was added. The mixture was cooled to 0° C. and sodium hydride (53 mg, 1.3 mmol, 60% in mineral oil) was added. The reaction was warmed to room temperature and stirred for 40 minutes, then was quenched with water, and extracted with EtOAc. The organic extract was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-70% EtOAc in hexanes afforded product (95 mg, 40%). 1H NMR (400 MHz, CDCl3) δ 7.14 (s, 1H), 6.79 (s, 1H), 5.27 (tt, J=7.7, 4.1 Hz, 1H), 4.44 (s, 2H), 4.44-4.38 (m, 2H), 3.80-3.68 (m, 2H), 3.58-3.47 (m, 2H), 3.31 (ddd, J=13.6, 8.5, 3.6 Hz, 2H), 1.99 (ddt, J=13.2, 6.3, 3.0 Hz, 2H), 1.78-1.67 (m, 2H), 1.47 (s, 9H); 19F NMR (376 MHz, CDCl3) 5-68.89 (s); LCMS (M+Na)+: 468.0.