Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:9]=1[Cl:10])([OH:4])=O.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[NH2:35])=[N:24][CH:25]=1>S(Cl)(Cl)=O.N1C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[NH:35][C:2]([C:5]2[S:6][CH:7]=[C:8]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]=2[Cl:10])=[O:4])=[N:24][CH:25]=1
Reactant: CN1CCN(Cc2csc(C(=O)O)c2Cl)CC1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CN1CCN(Cc2csc(C(=O)Nc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)c2Cl)CC1
Temperature: 25 °C
Reaction time: 90 h
Yield: 78.5 %

Procedure:
A suspension of 2-carboxy-3-chloro-4-(4-methylpiperazin-1-yl)methylthiophene HCl salt (2.0 g, 5.8 mmol) in thionyl chloride (50 mL) was heated at reflux. After 90 hours, the mixture was cooled to ambient temperature and concentrated of all volatiles in vacuo. To a suspension of the resulting solid in pyridine (20 mL) at 0° C was added N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide (1.5 g, 5.2 mmol) in pyridine (5 mL). The mixture was stirred and allowed to warm gradually to ambient temperature. After 16 hours, the mixture was concentrated of all volatiles in vacuo. Purification by flash chromatography on silica gel afforded 2.2 g (80% yield) of N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a tan foam; NMR (DMSO-d6 /TFA) 11.4 (s, 1), 11.0 (s, 1), 7.6-8.4 (m, 7), 4.4 (s, 2), 3.04.0 (br m, 8), 2.9 (s, 3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])CCC.CCCCCC.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>O1CCCC1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([CH3:9])=[CH:5][C:6]=2[Cl:8])=[O:27])=[CH:24][CH:23]=1
Reactant: Cc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
A stirred, -60° C. solution of 3,5-dichlorotoluene (805 mg, 5.00 mmol) in tetrahydrofuran (5 mL) under nitrogen atmosphere was treated dropwise over 10 minutes with a 1.6M solution of n-butyllithium in hexane (3.3 mL, 5.25 mmol). After addition was complete residual n-butyllithium in the addition funnel was rinsed into the reaction mixture with tetrahydrofuran (1 mL). The reaction mixture was stirred 30 minutes at -55° and then a solution of p-chlorobenzoylchloride (875 mg, 5.00 mmol) in tetrahydrofuran (1.0 mL) was added dropwise over 15 minutes. The mixture was kept at -55° to -30° C. for 2 hours, stirred 2 hours at ambient temperature, and quenched by addition of saturated aqueous ammonium chloride (1.1 mL). After stirring 15 minutes, sodium sulfate (1.1 g) was added, and the mixture was stirred an additional 15 minutes. The solution was decanted, the solids were washed with diethyl ether, and the combined solution and wash were evaporated under reduced pressure. The residue was recrystallized from ethanol (15 mL) to provide 0.78 g (52%) 4-(4-chlorobenzoyl)-3,5-dichlorotoluene.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:6][N:7]=1
Reactant: BrCC1CC1
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(OCC2CC2)cn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
To a solution of 6-bromopyridin-3-ol (5.00 g, 28.8 mmol) in DMF (50 mL) were added potassium carbonate (7.96 g, 55.6 mmol) and (bromomethyl)cyclopropane (4.18 mL, 43.1 mmol), and the mixture was stirred at 60° C. for 30 min. The reaction mixture was diluted with ethyl acetate, and the mixture was washed three times with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 1:1) to give the title compound (6.32 g, yield 96%) as an oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20](OCC)=[O:21])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[CH3:4][C:2]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)COc1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(OCCO)cc2)cc1
Yield: 25 %

Procedure:
2.2 g. (6.2 mMol) of the compound prepared in Example 31 in 50 ml. dry diethyl ether are heated with 1 g. lithium aluminium hydride, subsequently poured into water and a little 10% sulphuric acid, extracted with diethyl ether, dried over anhydrous sodium sulphate, filtered and the solvent removed in a vacuum. The residue is then recrystallised from toluene to give the title compound in a yield of 25% of theory; m.p. 136°-142° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]OS(C)(=O)=O)=[CH:33][C:32]=2[CH3:46])=[C:28]([CH:47]([CH3:49])[CH3:48])[NH:27][N:26]=1)(=O)C.[NH2:50][C:51]([CH3:55])([CH3:54])[CH2:52][OH:53].[I-].[Na+]>C(#N)C.C(O)C>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:50][C:51]([CH3:55])([CH3:54])[CH2:52][OH:53])=[CH:33][C:32]=3[CH3:46])=[C:28]([CH:47]([CH3:48])[CH3:49])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(C)(N)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: Cc1cc(OCCCNC(C)(C)CO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (1 g) in dichloromethane (16 mL) were added triethylamine (0.29 mL) and methanesulfonyl chloride (0.15 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole (1.12 g). The obtained 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole (0.2 g) was dissolved in a mixed solvent of acetonitrile (2 mL) and ethanol (2 mL). To the solution were added 2-amino-2-methyl-1-propanol (0.25 g) and a catalytic amount of sodium iodide, and the mixture was stirred at 60° C. for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.16 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (0.13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[CH:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1>[Hg].C1C=CC=CC=1.O1CCOCC1>[Cl-:1].[CH:16]1[C:15]2[N+:10]3[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[S:7][C:6]=3[CH:5]=[CH:4][C:3]=2[CH:2]=[CH:18][CH:17]=1
Reactant: Clc1ccccc1C=Cc1nc2ccccc2s1
Agent: [Hg]
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: [Cl-]
Product: c1ccc2c(c1)ccc1sc3ccccc3[n+]12

Procedure:
Exposure of dilute solutions of III in a benzene-dioxane (3:1) solution to a Hanovia 450 W mercury arc lamp for 24 h, using an internally cooled Vycor vessel, resulted in the formation of benzothiazolo[3,2-a]quinolinium chloride 1.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].Cl[C:6]1[C:7]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:8]=2[S:9][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=[O:12].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:28][C:26]1[CH:25]=[CH:24][C:8]2[S:9][C:10]([C:11]([NH:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)=[O:12])=[C:6]([S:4][CH:2]([CH3:3])[CH3:1])[C:7]=2[CH:27]=1
Reactant: CC(C)S
Reactant: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2Cl)cc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2SC(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
2-Propanethiol (32 μL, 0.35 mmol) is added to a solution of methyl 4-[[[3-chloro-5-methoxybenzo[b]thien-2yl]carbonyl]amino]benzoate (100 mg, 0.27 mmol) in 1 mL of DMF. Diazabicycloundecene (DBU) (52 μL, 0.35 mmol) is added and the mixture is stirred at room temperature for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane gives methyl 4-[[[5-methoxy-3-[(1-methylethyl)thio]benzo[b]thien-2yl]carbonyl]amino]benzoate in 72% yield; mp=157.5°-158.5° C.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:13]1([C:19]2[O:23][N:22]=[CH:21][C:20]=2[CH2:24][CH2:25][C:26](O)=[O:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH:10][C:26](=[O:27])[CH2:25][CH2:24][C:20]3[CH:21]=[N:22][O:23][C:19]=3[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A mixture of 4-(1-imidazolyl)aniline (0.51 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.60 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.75 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-(1-imidazolyl)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide (0.95 g, yield 83%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 176–177° C.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:16]=[CH:15][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH:7]=1.Cl.[C-:27]#[N:28].[Na+].C(=O)(O)[O-:31].[Na+]>O.CN(C)C=O>[C:27]([C:6]1[CH:16]=[CH:15][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:8]([CH:17]([OH:31])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH:7]=1)#[N:28]
Reactant: O=C([O-])O
Reactant: CS(=O)(=O)Nc1ccc(N)cc1Cc1ccc(F)cc1F
Reactant: [C-]#N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C#N)cc1C(O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of sodium nitrite (0.79 g) in water (5 ml) was added dropwise to a mixture of 4'-amino-2'-(2,4-difluorobenzyl)methanesulfonanilide (3.0 g) and hydrochloric acid (1.7 ml) in water (15 ml) at 0° to 5° C., and the solution was stirred for 20 minutes at the same temperature. The resulting solution was added dropwise to a mixture of sodium cyanide (1.7 g) and cupric sulfate pentahydrate (3.1 g) in water (25 ml) at 5 to 10° C. N,N-Dimethylformamide (30 ml) was added and the mixture was adjusted to pH 7 with sodium bicarbonate. The mixture was stirred at room temperature for 1 hour and at 60° C. for 4 hours. The reaction mixture was poured into ice-water (200 ml) and extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated. The residue (2.6 g) was purified by column chromatography on silica gel (80 g) eluting with a mixture of toluene and ethyl acetate (5:1) followed by recrystallization from ethanol to give prisms of 4'-cyano-2'-(2,4-difluoro-α-hydroxybenzyl)methanesulfonanilide (1.1 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([CH3:19])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([O-:23])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:19][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([C:2]3[CH:3]=[CH:4][CH:5]=[C:6]([CH:20]=[O:23])[CH:7]=3)[CH:7]=[CH:6][CH:5]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1cc(Nc2cccc(Br)c2)c2ccccc2n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2cccc(-c3cccc(C=O)c3)c2)c2ccccc2n1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
To a suspension of 71 (294 mg, 0.94 mmol) in toluene (9.6 mL) under N2 were sequentially added saturated NaHCO3 (aq. 3.8 mL), a solution of 72 (199 mg, 1.33 mmol) in EtOH (6.7 mL), and PdCl2(Ph3P)3 (32 mg, 0.046 mmol). The reaction was heated at 80° C. for 21 hours before it was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate (40 mL) and washed with water (15 mL), brine (15 mL). The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (dichloromethane to 20:1 dichloromethane/methanol) to give 73 as a yellow solid (219 mg, 68.9%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([NH2:27])[CH2:24][CH2:23][CH2:22]2>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([NH:27][C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=3)[N:3]=1)[CH2:24][CH2:23][CH2:22]2
Reactant: COc1cccc2c1C(N)CCC2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Product: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method described in example 2 from 2-chloro-6-nitro-quinoline and rac-8-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine (CAS no. 535935-61-6); MS: m/e=320.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl.Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 50 °C
Yield: 43.7 %

Procedure:
A solution of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.50 g) and 2-chloromethylquinoline hydrochloride (0.60 g) were suspended in 6 mL of dimethylformamide and 60% sodium hydride (0.224 g) was added. When gas evolution ceased, the bath temperature was raised to 50° C. for 2 hours. The reaction mixture was quenched with 0.1 mL of acetic acid and was diluted with ethyl acetate (75 mL). The mixture was washed with water (2×25 mL) and brine (1×25 mL), dried (MgSO4) and chromatographed over 100 g of silica gel, eluting with dichoromethane-ethyl acetate (50: 1) to give 0.39 g of 4-[(2-quinolinyl)methoxy]-alpha-oxobenzeneacetic acid methyl ester, mp 109°-110° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1.[CH3:23][O:24][C:25](=[O:28])[CH:26]=[CH2:27].C(N(CC)CC)C.CN(C)C=O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[CH2:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[CH2:16][CH2:17][CH2:18][N:12]1[C:4]1[CH:3]=[C:2](/[CH:27]=[CH:26]/[C:25]([O:24][CH3:23])=[O:28])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Clc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)/C=C/c1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
The mixture of 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (1.5 g, 4.86 mmol), acrylic acid methyl ester (0.88 ml, 9.7 mmol), triethylamine (6 mL) and N,N-dimethylformamide (6 mL), bis(tri-tert-butylphosphine)palladium(0) (124 mg, 0.243 mmol) was heated with stirring in a 20 mL of microwave process vial for 30 minutes at 100° C. under argon. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL×3). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo to give a residue which was purified by flash column to afford 1.41 g of product as a white solid (yield was 81%). MS obsd. (ESI+) [(M+H)+] 359.
Reaction SMILES: Br.[CH:2]1([S:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24]C)[N:15]=3)=[O:13])=[CH:8][CH:7]=2)[CH2:4][CH2:3]1.O>O1CCOCC1>[CH:2]1([S:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]([C:14]3[NH:15][C:16](=[O:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)=[O:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3]1
Reactant: COc1nc(C(=O)c2ccc(SC3CC3)cc2)ccc1C(F)(F)F
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(SC2CC2)cc1)c1ccc(C(F)(F)F)c(=O)[nH]1
Temperature: 65 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
48% hydrobromic acid (2 mL) was added to a solution of [4-(cyclopropylsulfanyl)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanone obtained in Reference Example 1-68 (400 mg) in 1,4-dioxane (4 mL), and the mixture was stirred at 65° C. for one hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:5) to give 6-{[4-(cyclopropylsulfanyl)phenyl]carbonyl}-3-(trifluoromethyl)pyridin-2(1H)-one (210 mg, 55%).
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3]Cl.[CH3:6][C:7]([CH3:13])([CH:10]=[C:11]=[CH2:12])[CH:8]=[O:9].[NH4+].[Cl-]>CCOCC>[CH3:1][C:2]([CH2:3][CH:8]([OH:9])[C:7]([CH3:13])([CH3:6])[CH:10]=[C:11]=[CH2:12])=[CH2:5]
Reactant: C=C(C)CCl
Reactant: C=C=CC(C)(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=C=CC(C)(C)C(O)CC(=C)C
Temperature: 15 °C
Yield: 91 %

Procedure:
300 ml of absolute ether were added to 7.29 g (0.30 mole) of dry Mg, the mixture was cooled to 15±1° C., and 27.19 g (0.30 mole) freshly distilled β-methylallyl chloride were added. The mixture was stirred over night at the same temperature. The white suspension was cooled to 0° C., and 11.03 g (0.10 mole) 1a in 150 ml absolute ether were added dropwise during 1 hour. The mixture was stirred at 0° C. for 4 hours (reaction monitored on GC). 37 ml of saturated NH4Cl solution were added with vigorous stirring. The solution was decanted from the magnesium salts which were washed several times with ether. The combined ether phases were dried (MgSO4). Distillation gave 14.22 g (91%) 2a, b.p. 60°-1° C./1.5 mm Hg.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([NH2:53])=[N:51][CH:52]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:35](=[O:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:51][CH:52]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(Cl)cn1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.5 %

Procedure:
A solution of triphenylphosphine (344 mg, 1.31 mmol) in methylene chloride (10 mL) cooled to 0° C. was treated with N-bromosuccinimide (263 mg, 1.48 mmol). The reaction solution was stirred at 0° C. for 5 min. At this time, 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)propionic acid (250 mg, 0.87 mmol) was added. The reaction was allowed to slowly warm to 25° C. over 45 min. At this time, 5-chloro-2-aminopyridine (145 mg, 1.13 mmol) and pyridine (0.11 mL, 1.31 mmol) were added to the reaction mixture. The reaction was stirred at 25° C. for 20 h. At this time, the reaction was diluted with water (10 mL) and extracted with methylene chloride (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded N-(5-chloro-pyridin-2-yl)3-cyclopentyl-2-(R)-(3,4-dichloro-phenyl)-propionamide (289 mg, 84%) as a white solid: mp 125-128° C.; [α]23589=−65.6° (c=0.16, chloroform); EI-HRMS m/e calcd for C19H19Cl3N2O (M+) 396.0563, found 396.0565.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][C:29](O)=[O:30])[C:14]3=[O:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CN(C(O[N:43]1N=N[C:45]2[CH:46]=CC=N[C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)CC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)[CH2:16][N:15]([CH2:28][C:29]([NH:43][CH2:44][CH2:45][CH3:46])=[O:30])[C:14]3=[O:32])=[CH:9][CH:8]=2)=[CH:33][CH:34]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)CN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCNC(=O)CN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)acetic acid (16.0 mg, 0.0326 mmol), HATU (18.6 mg, 0.0489 mmol) and iPr2NEt (17.0 μL, 0.0978 mmol) in DMF (0.5 mL) is added propylamine (5.36 μL, 0.0652 mmol). The reaction mixture is stirred at room temperature overnight before removal of the solvent. The residue is purified by preparative LC/MS to provide the title compound; HPLC-MS calculated for C27H25ClF3N3O3 (M+H+) 532.2, found 532.2.