Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[C:7]([C:16](=[O:19])[CH2:17][CH3:18])=[C:6]1[CH2:20][CH3:21].C[Sn]([N:30]=[N+:31]=[N-:32])(C)C.Cl>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[NH:32][N:31]=[N:30][N:15]=3)[CH:12]=2)[C:7]([C:16](=[O:19])[CH2:17][CH3:18])=[C:6]1[CH2:20][CH3:21]
Reactant: CCC(=O)c1c(CC)n(Cc2ccccc2Cl)c2cc(C#N)ccc12
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCC(=O)c1c(CC)n(Cc2ccccc2Cl)c2cc(-c3nnn[nH]3)ccc12
Temperature: 120 °C
Reaction time: 14 h
Yield: 64.1 %

Procedure:
To a solution of 1-(2-chlorobenzyl)-2-ethyl-3-propionylindole-6-carbonitrile (107 mg) in xylene (5 ml) was added trimethyltin azide (190 mg), and the mixture was stirred at 120° C. for 14 hours. The resulting mixture was poured into 1N HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 20% methanol in chloroform to give 1-(2-chlorobenzyl)-2-ethyl-3-propionyl-6-(1H-tetrazol-5-yl)indole (77 mg) as a solid.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[B-](F)(F)(F)F.[CH3:22][CH2:23][O+](CC)CC>C(Cl)Cl>[CH2:1]([O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](=[NH:12])[O:11][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccccc1C(N)=O
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCCCCOc1ccccc1C(=N)OCC
Reaction time: 48 h

Procedure:
To a solution of 2-hexyloxybenzamide (64 g; prepared as described by E. M. Bavin, F. J. Macrae, D. E. Seymour and P. D. Waterhouse, J.Pharm.Pharmacol., 1952, 4, 872) in anhydrous methylene chloride (830 ml.) was added, dropwise during 10 minutes with stirring, a solution of triethyloxonium borofluoride (55.2 g.) in anhydrous methylene chloride (170 ml.). The solution was stirred for a further 105 minutes, and allowed to stand at room temperature for 2 days. The solution was concentrated to 350 ml., and anhydrous diethyl ether (1750 ml.) was added. The precipitated solid was filtered off and washed with anhydrous diethyl ether to give ethyl 2-hexyloxybenzimidate borofluoride (62 g.), m.p. 68°-70° C., which was pure enough to use for the next stage of the synthesis. A pure sample, m.p. 73°-74° C., was obtained by recrystallisation of an aliquot from a mixture of anhydrous methylene chloride and anhydrous diethyl ether.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:6]=1.[OH-].[K+].O>C(O)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:26])=[O:2])=[CH:6][CH:7]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1
Yield: 84.1 %

Procedure:
The title compound is prepared by the procedure of Example 32 using 75 g of product from Example 51, 34.8 g of potassium hydroxide, 45 ml of water and 800 ml of ethyl alcohol. The residue is recrystallized from carbon tetrachloride/hexane to give 60.6 g of the desired product as white crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:18][C:12]2[C:11]3[C:16](=[CH:17][C:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[N:15]=[CH:14][N:13]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(COc2ncnc3cc(Br)ccc23)cc1
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(COc2ncnc3cc(N4CCOCC4)ccc23)cc1
Yield: 81.7 %

Procedure:
Under a nitrogen atmosphere, 2.82 g (12.5 mmol) of tris(dibenzylideneacetone)dipalladium-(0) and 5.41 g (15.1 mmol) of 2-(dicyclohexylphosphino)biphenyl were dissolved in 1.5 l of toluene, and 269.0 ml (3.1 mol) of morpholine and 213.0 g (0.62 mol) of 7-bromo-4-(4-methoxybenzyloxy)quinazoline [dissolved in 2 l of toluene] were added successively. 73.0 g (0.8 mol) of sodium tert-butoxide were subsequently added in portions, and the mixture was stirred. Conventional work-up gave 178 g of 4-(4-methoxybenzyloxy)-7-morpholin-4-ylquinazoline; HPLC/MS (M+H)+=350 as oil [crude product; was reacted further directly].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].C1(C)C=CC(S(O[CH2:21][C@@H:22]2[O:24][CH2:23]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:21][C@@H:22]2[O:24][CH2:23]2)[C:3]=1[CH:4]=[O:5]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: O=Cc1c(O)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)cccc1OC[C@H]1CO1
Temperature: 60 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
A stirred mixture of 2-chloro-6-hydroxybenzaldehyde (4.4 g), (R)-glycidyl 4-toluenesulphonate (5.0 g) and potassium carbonate (3.9 g) in dimethylformamide (120 ml) was heated at 60° C. for 5 hours then allowed to stand at ambient temperature for 18 hours. The solvent was removed in vacuo, water (60 ml) was added and the mixture extracted with ether (3×100 ml). The combined extracts were dried over magnesium sulphate and the solvent evaporated. The residue was purified by flash chromatography on silica eluting with a 1:1 mixture of petroleum ether (b.p. 60-80° C.) and dichloromethane followed by a 19:1 mixture of dichloromethane and industrial methylated spirit. Appropriate fractions were combined and the solvent was removed in vacuo to give (R)-2-chloro-6-(2,3-epoxypropoxy)benzaldehyde (2.8 g) m.p. 62-64° C.
Reaction SMILES: CO.[NH3:3].[C:4]([NH:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[S:16](Cl)(=[O:18])=[O:17])(=[O:6])[CH3:5]>CO.O1CCCC1>[F:15][C:13]1[CH:12]=[CH:11][C:10]([S:16](=[O:18])(=[O:17])[NH2:3])=[C:9]([CH:14]=1)[CH2:8][NH:7][C:4](=[O:6])[CH3:5]
Reactant: CC(=O)NCc1cc(F)ccc1S(=O)(=O)Cl
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)NCc1cc(F)ccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Step 2) To a solution of 8N ammonia methanol solution (2 ml) in methanol (15 ml) was added dropwise a suspension of 2-[(acetylamino)methyl]-4-fluorobenzenesulfonyl chloride obtained in Step 1 (1.34 g) in tetrahydrofuran (5 ml) under ice-cooling, and the mixture was allowed to warm to room temperature, and stirred for 1 hr. The reaction mixture was quenched with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give N-(5-fluoro-2-sulfamoylbenzyl)acetamide (1.34 g) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:21]([N:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:7]=2[CH3:20])[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(SCCCN2CCN(Cc3ccccc3)CC2)ccnc1CSc1ccncc1
Yield: 57 %

Procedure:
According to the procedure indicated in Example 7, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 1-benzylpiperazine and potassium carbonate in acetonitrile, after chromatography on silica gel and crystallization of the concentrated pure fraction from diisopropyl ether, gives the title compound as a colorless solid; m.p. 79-81° C.; yield 57% of theory. A hydrated hydrochloride can be prepared from isopropanol; m.p. 165° C. (dec.); yield 87% of theory.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][CH:17]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)Cc3ccccc3)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NC(=O)Cc2ccccc2)cc1
Yield: 85 %

Procedure:
To a mixture of methyl 3,3-dimethyl-2-(4-(2-phenylacetamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (90 mg, 0.21 mmol) in methanol (3 mL) and water (1.5 mL) was added a solution of sodium hydroxide (143 mg, 3.57 mmol.) in water (1.5 mL). The resultant mixture was heated to reflux until the completion of the reaction (monitored by Thin layer chromatography). The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=1. The precipitates were collected by filtration to afford 3,3-dimethyl-2-(4-(2-phenylacetamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid, 75 mg, Yield 85% MS (ESI+APCI) M+1=415.6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=[CH:36][CH:37]=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1(CN)CC1>CN(C=O)C>[CH:35]1([CH2:34][NH:30][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:16][CH:17]=2)[CH2:37][CH2:36]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NCC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (60 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and cyclopropanemethylamine (0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (45 mg, 65%) which was obtained as a white solid. MS: m/e=382.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[O:6]C(=O)[CH:4]=1.[CH3:14][O-:15].[Mg+2].[CH3:17][O-:18]>>[F:10][C:9]([F:11])([F:12])[C:7](=[O:6])[CH2:8][C:3]([O:2][CH3:1])=[CH:4][C:14]([O:18][CH3:17])=[O:15]
Reactant: C[O-]
Reactant: COc1cc(C(F)(F)F)oc(=O)c1
Agent: [Mg+2]
Product: COC(=O)C=C(CC(=O)C(F)(F)F)OC
Yield: 82.5 %

Procedure:
A solution of 4-methoxy-6-trifluoromethylpyran-2-one (2.7 g, 14 mmol) in a methanolic magnesium methanolate solution (8.5% Mg(OMe)2, 8.36 g, 8 mmol) was heated under reflux for 16 hours. The solution was concentrated and taken up in water and ethyl acetate, and the organic phase was brought to pH 5 by adding dilute hydrochloric acid. The organic phase was separated off, dried and concentrated. 1.5 g of crude product were obtained as a yellow oil. Kugelrohr distillation at 0.04 mbar and about 160° C. afforded methyl 6,6,6-trifluoro-3-methoxy-5-oxo-2-hexenoate (1.50 g, 6.6 mmol, 48%) as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH2:2]1.[CH3:17][S:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[CH3:17][S:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]3[C:8]4[CH:9]=[CH:10][N:11]=[CH:12][C:13]=4[CH:14]=[CH:15][CH:16]=3)[CH2:2]2)=[CH:21][CH:20]=1
Reactant: c1cc(N[C@@H]2CCNC2)c2ccncc2c1
Reactant: CSc1ccc(C=O)cc1
Product: CSc1ccc(CN2CC[C@@H](Nc3cccc4cnccc34)C2)cc1

Procedure:
Reaction of (R)—N-(pyrrolidin-3-yl)isoquinolin-5-amine and 4-(methylthio)-benzaldehyde using the method of Example 8 afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:12]2[S:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[K+].[K+].Cl[CH2:34][C:35](Cl)=[O:36].O1C=CCC(=O)N1>CN(C=O)C.[Cl-].[NH4+]>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:11]([C:12]2[S:16][N:15]=[CH:14][N:13]=2)[S:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:35](=[O:36])[CH2:34][O:26][C:3]=3[CH:4]=2)(=[O:9])=[O:10])=[CH:19][CH:20]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(N)c(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: O=C1CC=CON1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)OCC(=O)N3)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50.8 %

Procedure:
A 250 mL round bottom flask was charged with 4-amino-3-hydroxy-N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (INTERMEDIATE J, 2.450 g, 6.24 mmol) and K2CO3 (2.59 g, 18.73 mmol), and diluted with DMF (62.4 mL) under an inert atmosphere. The reaction mixture was cooled to 0° C. in an ice-water bath, and 2-chloroacetyl chloride (0.596 mL, 7.49 mmol) was added (color change from orange to light yellow suspension). After stirring for 5 minutes, the reaction was warmed to rt. After 30 minutes, complete conversion to the first alkylation was observed (M+H=468), along with some fully cyclized material. The reaction was heated to 50° C. for 2 h until complete conversion to the cyclized oxazinone. The reaction was cooled to rt, and diluted with sat aq. ammonium chloride and then extracted with ethyl acetate. The organics were washed with brine, then dried over magnesium sulfate and concentrated under a vacuum. Upon attempts to transfer using DCM and a small amount of ether, it was observed that a solid crashed out of solution. The solids were filtered, and washed with ether to yield 1.37 g of N-(4-methoxybenzyl)-3-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE K) as a light pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3 H) 4.67 (s, 2 H) 5.13 (s, 2 H) 6.83-6.92 (m, 2 H) 7.04 (d, J=8.41 Hz, 1 H) 7.30 (d, J=8.80 Hz, 2 H) 7.37 (d, J=2.05 Hz, 1 H) 7.56 (dd, J=8.41, 2.15 Hz, 1 H) 8.41 (s, 1 H) 11.21 (s, 1 H). m/z (ESI) 432.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29]>>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)cc2)c1)c1ccc(Cl)nc1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccc(Cl)cc4)c3)cn2)CC1

Procedure:
6-chloro-N-(4-chloro-3-(4-chlorobenzamido)phenyl)nicotinamide (0.16 mmol) was used in general procedure 3 with 1-acetylpiperazine (0.83 mmol). The product was purified by RP-HPLC to give 6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(4-chlorobenzamido)phenyl)nicotinamide. MS (Q1) 512.3 (M)+
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22]3)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:35][C:36]1[C:37]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[Cl:35][C:36]1[C:37]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:38]=2[S:39][C:40]=1[C:41]([N:20]([CH2:19][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:23][CH2:22]1)=[O:42]
Reactant: COc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1CNC1CCC(NC(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(NC(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 225 (502 mg, 1.02 mmol) is treated with acid chloride 8 (301 mg, 1.13 mmol) using Method D to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([N+:25]([O-:27])=[O:26])[CH:3]=1.[CH3:28][O:29][C:30]1[C:35]([CH3:36])=[C:34](B(O)O)[C:33]([CH3:40])=[CH:32][N:31]=1.C(OCC)(=O)C.O>O1CCOCC1>[O:18]1[CH2:19][CH:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[C:33]([CH3:40])=[CH:32][N:31]=[C:30]([O:29][CH3:28])[C:35]=4[CH3:36])=[CH:3][C:4]=3[N+:25]([O-:27])=[O:26])=[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]=[N:11]2)[CH2:14][O:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cnn(C2COCCOC2)c1-c1ccc(Br)cc1[N+](=O)[O-]
Reactant: COc1ncc(C)c(B(O)O)c1C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(C2COCCOC2)c1-c1ccc(-c2c(C)cnc(OC)c2C)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 6.75 h
Yield: 155.5 %

Procedure:
Water (0.2 mL), (2-methoxy-3,5-dimethylpyridin-4-yl)boronic acid (39.5 mg) obtained in Preparation Example 29, Pd(PPh3)4 (10.5 mg) and cesium carbonate (178 mg) were added to a solution of ethyl 5-(4-bromo-2-nitrophenyl)-1-(1,4-dioxepan-6-yl)-1H-pyrazole-4-carboxylate (80 mg) obtained in Preparation Example 9-(2) in 1,4-dioxane (1.3 mL), and the reaction mixture was stirred at 100° C. for 6.75 hours. (2-methoxy-3,5-dimethylpyridin-4-yl)boronic acid (15 mg) was added to the reaction mixture and the reaction mixture was stirred at 100° C. for 2.5 hours. After the reaction mixture was returned to mom temperature, ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, ethyl acetate/n-heptane, 20 to 33%) to give the title compound (64 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[C:3]1=[O:24].C(N(CC)CC)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:46])([F:45])[F:44])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CCO>[CH:15]([N:13]([CH3:14])[C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:45])([F:46])[F:44])[CH:41]=4)[N:36]=[CH:35][N:34]=3)[C:3]2=[O:24])[C@H:8]([CH2:18][S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:9]1)([CH3:17])[CH3:16]
Reactant: CCS(=O)(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCS(=O)(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 80 °C
Yield: 63 %

Procedure:
To a solution of (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (50 mg, 0.1 mmol) in EtOH (2 mL) was added triethylamine (0.1 mL, 0.6 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (27 mg, 0.11 mmol). The mixture was heated at 80° C. for 14 h and then concentrated in vacuo. The residue was purified by HPLC to provide the title compound, (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one (35 mg). MS found: (M+H)+=556.
Reaction SMILES: Cl.C(N=C=N[CH2:7][CH2:8][CH2:9]N(C)C)C.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][C:23]([OH:25])=[O:24])[CH:20]=2)[CH:15]=[CH:14]1.C(O)C=C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][C:23]([O:25][CH2:9][CH:8]=[CH2:7])=[O:24])[CH:20]=2)[CH:15]=[CH:14]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cc1ccc2cc[nH]c2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C=CCO
Product: C=CCOC(=O)Cc1ccc2cc[nH]c2c1
Yield: 86.8 %

Procedure:
750 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to a solution of 450 mg of 2-(indol-6-yl)acetic acid [synthesized according to the procedures described in Chem. Pharm. Bull., 20, 2163 (1972)], 0.27 ml of allyl alcohol and 480 mg of 4-dimethylaminopyridine in 20 ml of methylene chloride, at room temperature, and the resulting mixture was stirred overnight. After completion of the reaction, the reaction mixture was acidified by the addition of a 3% aqueous solution of hydrochloric acid, followed by extraction with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 10 g of silica gel with a 4:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 480 mg of the title compound as an oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:11][CH:12]=2)=[CH:17][CH:18]=1)[CH3:28]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)COc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1

Procedure:
Benzyl bromide (0.23 mL) was added to a mixture of ethyl (4′-hydroxybiphenyl-4-yloxy)acetate (0.50 g) and potassium carbonate (0.38 g) in N,N-dimethylformamide (5 mL) at room temperature with stirring, and the mixture was stirred at that temperature for 1 hr. Benzyl bromide (0.021 mL) was added to the reaction mixture. After being stirred for 30 minutes, benzyl bromide (0.044 mL) was added, and the mixture was stirred for 30 minutes. The reaction mixture was partitioned between methylene chloride and water, and the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3-1/2-2/1) to afford the title compound (0.64 g).