Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:25][CH2:26][O-:27].[Na+].CCO>O>[CH2:26]([O:27][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1)[CH3:25]
Reactant: CC[O-]
Reactant: CCc1cccc(NC(=O)Nc2csc(-c3ccnc(Cl)c3)n2)n1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cc(-c2nc(NC(=O)Nc3cccc(CC)n3)cs2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 10 mL round bottom flask containing 1-[2-(2-chloropyridin-4-yl)thiazol-4-yl]-3-(6-ethylpyridin-2-yl)urea (40 mg, 0.11 mmol) (prepared similar to that described for Example 95) was charged a 21 wt % NaOEt/EtOH solution (5 mL). The reaction mixture was heated to reflux. After 2 h, the reaction mixture was cooled to RT and diluted with H2O then concentrated in vacuo. The solid residue was washed with CH2Cl2 and EtOAc then the solid was diluted with MeOH and concentrated in vacuo. The residue was diluted with EtOAc; washed with saturated NH4Cl and H2O, dried (MgSO4) and concentrated in vacuo to afford the title compound as a light-orange solid. MS m/z: 370.2 (M+H). Calc'd for C18H19N5O2S: 369.13.
Reaction SMILES: [OH-:1].[K+].[Br:3][C:4]1[C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:6][C:7]([O:12][CH2:13][CH3:14])=[C:8]([CH:11]=1)[C:9]#N.C1C[O:25][CH2:24][CH2:23]1.Cl>C(O)C>[Br:3][C:4]1[C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:6][C:7]([O:12][CH2:13][CH3:14])=[C:8]([CH:11]=1)[C:9]([O:25][CH2:24][CH3:23])=[O:1]
Reactant: CCOc1nc(-c2ccc(F)cc2)c(Br)cc1C#N
Reactant: C1CCOC1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc(Br)c(-c2ccc(F)cc2)nc1OCC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
An 8 M aqueous potassium hydroxide solution (14.6 mL) was added to a mixture of 5-bromo-2-ethoxy-6-(4-fluorophenyl)nicotinonitrile (3.75 g), THF (10 mL), and ethanol (10 mL), and the resultant mixture was stirred overnight at 100° C. The reaction mixture was neutralized with 6 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. Potassium carbonate (3.23 g) and iodoethane (1.40 mL) were added to a mixture of the obtained residue and DMF (10 mL), and the resultant mixture was stirred at 60° C. for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.40 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](OC)=[C:24]([C:27]#[N:28])[C:25]#[N:26])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].[H-].[Na+]>CN(C)C=O>[C:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]3[N:1]([C:27](=[NH:28])[C:24]=2[C:25]#[N:26])[CH:6]=[CH:5][CH:4]=[CH:3]3)=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: CCOC(=O)Cc1ccccn1
Reactant: COC(=C(C#N)C#N)c1ccc(OC(C)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(OC(C)=O)cc2)c(C#N)c(=N)n2ccccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A mixture of 165 mg of ethyl 2-pyridylacetate and 242 mg of 3-(4-acetoxyphenyl)-2-cyano-3-methoxyacrylonitrile was dissolved in 1 ml of dry N,N-dimethylformamide. To the solution was added 40 mg of 60% sodium hydride at room temperature and the reaction mixture was stirred for 1 hour at 60° C. The reaction mixture was poured into ice-water, and precipitated crystals were collected by filtration, washed with water and dried to obtain 120 mg of 2-(4-acetoxyphenyl)-3-cyano-1-ethoxycarbonyl-4-imino-4H-quinolizin. The obtained imine compound was added to 5 ml of 90% acetic acid and the reaction mixture was heated under reflux for 72 hours. After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, and the solution was washed successively with 1N-hydrochloric acid, water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was recrystallized from methanol to obtain 75 mg of 3-cyano-1-ethoxycarbonyl-2-(4-hydroxyphenyl)-4H-quinolizin-4-one.
Reaction SMILES: C[C:2]([C:4]1C=C[C:7](O)=[CH:8][CH:9]=1)=[O:3].[NH2:11][CH2:12][CH2:13][CH2:14][Si](OCC)(OCC)OCC.C=O>C1(C)C=CC=CC=1>[O:3]1[C:2]2[CH:4]=[CH:9][CH:8]=[CH:7][C:14]=2[CH:13]=[CH:12][NH:11]1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: C=O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Yield: 55 %

Procedure:
This compound was prepared according to the method used for the previous examples by combining 4-hydroxyacetophenone (13.6 g, 100 mmol), 3-aminopropyltriethoxysilane (22.1 g, 100 mmol), paraformaldehyde (6.3 g, 210 mmol), and toluene (150 mL). The final product was a clear, almost colorless liquid. The yield was 55%.
Reaction SMILES: [Zn:1].[Br:2]CCBr.C[Si](Cl)(C)C.[Cl:11][C:12]1[C:13]([F:20])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br>O1CCCC1>[Br-:2].[Cl:11][C:12]1[C:13]([F:20])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][Zn+:1]
Reactant: BrCCBr
Reactant: [Zn]
Reactant: Fc1c(Cl)cccc1CBr
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: Fc1c(Cl)cccc1C[Zn+]
Product: [Br-]
Reaction time: 0.5 h

Procedure:
Under a nitrogen stream, zinc powder (18.8 kg, 287 mol) was suspended in tetrahydrofuran (130 L), 1,2-dibromoethane (470 g, 2.50 mol) was added at 60° C., and the mixture was stirred at the same temperature for 30 min. Trimethylsilyl chloride (560 g, 3.10 mol) was added to this suspension at room temperature, and the mixture was stirred with heating for 30 min. A solution of 3-chloro-2-fluorobenzyl bromide (54.0 kg, 242 mol) in tetrahydrofuran (65 L) was added dropwise at 0° C., and the mixture was stirred at 20° C. for 3 hr. The remaining zinc was filtered off to give a solution of 1M 3-chloro-2-fluorobenzylzinc bromide in tetrahydrofuran. This was used in the next main step.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=O)[C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:19])[CH:2]=1.C(O)(C)C.CCCCCC>C(O)(=O)C.C(O)(C)C.[Pd]>[CH:5]1[C:6]([C@H:7]2[CH2:8][O:9][C:10]3[CH:11]=[C:12]([OH:18])[CH:13]=[CH:14][C:15]=3[CH2:16]2)=[CH:1][CH:2]=[C:3]([OH:19])[CH:4]=1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: CCCCCC
Product: Oc1ccc([C@H]2COc3cc(O)ccc3C2)cc1

Procedure:
Daidzein (200 mg, 0.8 mmol) is dissolved in a mixture of glacial acetic acid (20 mL) and isopropanol (20 mL), and is reduced with 10% Pd on charcoal (150 mg) at 55 p.s.i.g. (3.7 atm gauge). At the end of the reaction (2 hours, TLC:isopropanol/n-hexane 1/4) the catalyst is filtered off, and the filtrate is evaporated. The crude residue is purified by chromatography on a silica gel column using as eluent a mixture of isopropanol and n-hexane (1:4 v/v), to give (±) equol as a pure product (160 mg, yield: 82%) crystallized from n-hexane. The product, colorless crystals, is not hygroscopic, is stable in air, and does not decompose during the final filtration procedure. The product of this chemical synthesis was in all respects identical with an authentic sample of (±) equol (racemic equol). FIG. 4 shows the GC-MS analysis of the trimethylsilyl ether derivative of synthesized product as a single pure peak and a mass spectrum that is consistent with the published electron ionization spectrum of the trimethylsilyl (TMS) ether derivative of authentic equol. The molecular ion as expected is at m/z 470 and the base peak at m/z 234. The purified equol product had a purity of greater than 99%, as confirmed by HPLC and mass spectrometry.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].Cl.[CH3:15][NH:16][CH3:17].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:15][N:16]([CH3:17])[C:11]([C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]1)=[O:13]
Reactant: CNC
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](C(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (20.0 g) obtained in Reference Example 1(2) is dissolved in chloroform (200 ml), and thereto are added dimethylamine hydrochloride (10.5 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (24.7 g) and triethylamine (26.0 g) under ice-cooling. The mixture is then stirred at room temperature for 17 hours. Ice-water is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine successively and dried over sodium sulfate. The solvent is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent: chloroform, followed by chloroform/methanol=20/1) to give methyl trans-4-[(dimethylamino)carbonyl]-cyclohexanecarboxylate (20.1 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[OH:10].[OH-].[Na+]>O.CC(OC)(C)C>[CH3:1][C:2]1[C:3](=[O:10])[CH:4]=[CH:5][C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: Cc1c(O)ccc(O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CC1=C(C)C(=O)C=CC1=O
Temperature: 50 °C
Yield: 88.1 %

Procedure:
A solution of FeCl3.6H2O (81.0 g, 300 mmol) in water (100 mL) was added to a solution of 2,3-dimethyl-benzene-1,4-diol (13.8 g, 100 mmol) in MTBE (150 ml) at ambient temperature. Aqueous sodium hydroxide solution (2.5M, 60 mL, 150 mmol) was added to the vigorously stirring mixture and the reaction heated to 50° C. for 5 hrs. MTBE (150 mL) and water (150 mL) were added and the aqueous layer further extracted with MTBE (2×100 mL). The combined organics were washed with brine (100 mL), dried (Na2SO4), and concentrated to give the intermediate 2,3-dimethyl-[1,4]benzoquinone as an orange-yellow solid (12.0 g, 88%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:5][C:6]1[C:13]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O)[CH3:4].[BH4-].[Na+]>CO>[CH2:3]([O:5][C:6]1[C:13]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][CH2:1][NH2:2])[CH3:4]
Reactant: CN
Reactant: CCOc1c(C=O)cccc1OC(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1c(CCN)cccc1OC(F)(F)F
Reaction time: 18 h
Yield: 58 %

Procedure:
A solution of methylamine (20 mL of a 2.0 M solution if MeOH, 40 mmol) was added to 2-ethoxy-3-trifluoromethoxybenzaldehyde (1.17 g, 4.95 mmol) under N2 and the solution was stirred for 18 h. The solution was concentrated under reduced pressure. The resulting clear oil was dissolved in EtOH (20 mL) and treated with NaBH4 (0.187 g, 4.95 mmol). After stirring for 5.5 h, the reaction mixture was concentrated under reduced pressure, then dissolved in 1 N NaOH (20 mL) and extracted with Et2O (3×50 mL). The combined organics were collected, washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (0.72 g, 58%) as a clear oil: 1H NMR (500 MHz, DMSO-d6) δ 7.40 (dd, J=7.7, 1.55 Hz, 1H), 7.25 (d, J=9.5 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H), 3.97 (t, J=7.0 Hz, 2H), 3.68 (s, 2H), 2.28 (s, 3H), 2.02 (br s, 1H), 1.35-1.30 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: OB(O)c1ccc(F)cc1F
Product: COc1cccc2c(-c3ccc(F)cc3F)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2,4-difluoro-phenylboronic acid to give [1-(2,4-difluoro-phenyl)-5-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: [OH-].[Na+].CC1(C)C(C)(C)OB([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)O1.Br[C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28]>[Pd].C1COCC1>[NH:15]1[C:16]2[C:12](=[C:11]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([CH:30]=3)[C:27]([OH:29])=[O:28])[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: O=C(O)c1cncc(Br)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cncc(-c2cccc3[nH]ccc23)c1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
Palladium catalyst Pd(PPh3)4 (693 mg, 0.6 mmol) and freshly prepared aqueous sodium hydroxide (3.2 g in 29 mL of water) were added to a mixture of 4-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-1H-indole (4.9 g, 20.2 mmol) and 5-bromonicotinic acid (4.04 g, 20 mmol) in THF (70 mL). The system was degassed and then purged three times with nitrogen. The mixture was refluxed under nitrogen for 6 hours. It was then cooled to room temperature and ethyl acetate (400 mL) added. The organic layer was separated and washed twice with 2N NaOH solution. The aqueous layer and hydroxide washes were combined, washed with dichloromethane and then acidified with 6N HCl. The resulting precipitate was collected by vacuum filtration, washed with water and dried to give 2.3 g (48%) 5-(1H-indol-4-yl)-nicotinic acid.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25]([C:27]1C=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[OH:26].[Li+].CC([N-:38]C(C)C)C.ClC1C=CC(C=O)=NC=1>C1COCC1.CC(=O)OCC.O>[Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25]([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][N:38]=1)[OH:26]
Reactant: CC(C)[N-]C(C)C
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)cnc21
Agent: O=Cc1ccc(Cl)cn1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cn3)c(Br)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 138.9 %

Procedure:
To a solution of 6-bromo-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 20, step 4, 398 mg, 0.10 mmol) in THF (10 mL) at −78° C. was added LDA (2M in THF, 2.50 mL, 5.00 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 5-chloropicolinaldehyde (211 mg, 1.50 mmol) in THF (2 mL) was added. The reaction was stirred at −78° C. for 40 min then diluted with EA (20 mL) and water (10 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (8:1) to give 6-bromo-5-((5-chloropyridin-2-yl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (75 mg, 13.9% yield) as a solid. LCMS: MH+ 541 and TR=1.773 min.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)C.ClC(N(C)C)=C(C)C.N1C=CC=CC=1.[NH2:37][C:38]1[N:42](C(OC(C)(C)C)=O)[N:41]=[C:40]([O:50][CH2:51][C:52]2[CH:57]=[C:56]([O:58][CH3:59])[CH:55]=[C:54]([O:60][CH3:61])[CH:53]=2)[CH:39]=1.Cl.O1CCOCC1>C1COCC1>[CH3:59][O:58][C:56]1[CH:57]=[C:52]([CH2:51][O:50][C:40]2[CH:39]=[C:38]([NH:37][C:20]([C:17]3[CH:18]=[N:19][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][CH:16]=3)=[O:22])[NH:42][N:41]=2)[CH:53]=[C:54]([O:60][CH3:61])[CH:55]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Reactant: COc1cc(COc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCNCC4)nc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
6-[4-[(2-Methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]pyridine-3-carboxylic acid (150 mg, 0.412 mmol) was dissolved in dry THF (10 ml), 1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (65 μl, 0.412 mmol) was added and the mixture was stirred at room temperature under nitrogen overnight. Pyridine (40 μl, 0.412 mmol) and tert-butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (142 mg, 0.343 mmol) were added and the mixture was stirred at 65° C. for 18 h. The mixture was then cooled to room temperature and stirred overnight with 4 M HCl in dioxane (1.8 ml, 7.20 mmol). The mixture was then filtered and the solid was washed with hexane. The product was purified on acidic prep. HPLC, eluting with a gradient of 16-26% MeCN in water (containing 0.1% TFA). The product containing fractions were neutralised with aq. NaHCO3 and the acetonitrile removed under vacuum. The product precipitated out and was collected by filtration. This was further washed with water and dried in vacuo to give the title compound (39 mg, 26%) as a white solid; 1H NMR (399.902 MHz, DMSO) δ 2.82 (t, J=5.1 Hz, 4H), 3.61 (t, J=4.8 Hz, 4H), 3.80 (s, 6H), 5.13 (s, 2H), 5.62 (bs, 1H), 6.50 (s, 1H), 6.65 (d, J=2.2 Hz, 2H), 6.92 (d, J=8.9 Hz, 1H), 8.09 (d, J=9.3 Hz, 1H), 8.76 (d, J=2.3 Hz, 1H), 10.74 (bs, 1H), 11.64 (bs, 1H). MS: m/z=439 (MH+)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH3:13][C@@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]=1[NH:21][C@@H:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCOCC1=O
Reactant: C[C@@H](N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)COCC1
Yield: 104.2 %

Procedure:
A solution of 3-oxo-tetrahydro-pyran-4-carboxylic acid ethyl ester (3.03 g, 17.6 mmol), R-(+)-α-methylbenzylamine (2.35 g, 19.4 mmol) and p-toluenesulfonic acid hydrate (67 mg, 230 μmol) in benzene (60 mL) was heated at reflux under a Dean-Stark trap for 16 h. The cooled mixture was concentrated in vacuo to provide the product as a yellow oily semisolid (5.05 g), used without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:16]#N.Cl.CC[O:26]CC>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:16]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:26]
Reactant: COc1ccc(C#N)cc1OC
Reactant: c1ccoc1
Reactant: CCOCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccco2)cc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Freshly distilled furan (57 ml, 790 mmoles) in dry ether (500 ml) is cooled (5° C) under nitrogen and n-butyllithium (340 ml, 2.35M in hexane) is added dropwise to the stirred solution. The mixture is stirred for 3 days at room temperature. The mixture is cooled to -30° C and a solution of 3,4-dimethoxybenzonitrile (77.5 g, 480 mmoles, described in Example I) in ether (200 ml) is added dropwise to the mixture. The brown mixture is stirred for 5 hours at room temperature. Wet tetrahydrofuran is cautiously added and the mixture is poured on ice. Hydrochloric acid (3N) is added until the mixture is acidic. The mixture is extracted with ether. The aqueous phase is rendered basic and extracted with methylene chloride. The organic extract is washed with brine, dried and evaporated. The residue is subjected to chromatography on silica gel using chloroform and the eluates are evaporated to give the title compound, mp 112°-114° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:35][C:36]1[C:37]2[CH:47]=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[Cl:35][C:36]1[C:37]2[CH:47]=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41]([N:19]([CH2:18][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][CH3:17])[CH:20]1[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:22][CH2:21]1)=[O:42]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: CCOc1ccc(-c2cccc(C#N)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CCOc1ccc(-c2cccc(C#N)c2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 81 (390 mg, 0.84 mmol) is treated with 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (233 mg, 1.01 mmol) using Method D to give the title compound.
Reaction SMILES: C1[C:7](=[O:8])[NH:6][C:4](=O)[N:3]([CH:9]2[O:13]C(COP(OC3C(O)C(N4C(=O)NC(=O)C=C4)OC3CO)(O)=O)C(O)C2O)C=1.[NH3:38].OC1C=CC(CC(O)=O)=CC=1.[NH2:50][CH2:51][C:52]([OH:54])=O>>[NH:38]1[C:52](=[O:54])[C:51]2[NH:50][C:7](=[O:8])[NH:6][C:4]=2[NH:3][C:9]1=[O:13]
Reactant: N
Reactant: O=c1ccn(C2OC(COP(=O)(O)OC3C(CO)OC(n4ccc(=O)[nH]c4=O)C3O)C(O)C2O)c(=O)[nH]1
Reactant: NCC(=O)O
Agent: O=C(O)Cc1ccc(O)cc1
Product: O=c1[nH]c(=O)c2[nH]c(=O)[nH]c2[nH]1

Procedure:
, the reagent solution contains, uricase 300 units/ml, horse radish peroxidase 100 micrograms/ml, and p-hydroxy phenyl acetic acid 100 micrograms/ml, dissolved in 0.1 mol/L glycine buffer pH 9.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](F)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1([S:8]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)(=[O:10])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(F)c1cccc(Br)c1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a stirred solution of 3-bromophenylsulfonyl fluoride (D1) (1 g, 4.18 mmol) in dry THF (20 ml) at −78° C., under argon was added phenylmagnesium bromide (1M, 1.4 ml, 4.18 mmol) dropwise. The reaction was left to warm to room temperature overnight and then quenched with ammonium chloride (50 ml), extracted with ethyl acetate (3×40 ml) and the combined organic extracts dried (Na2SO4). Solvents were evaporated in vacuo to give a colourless solid (1.09 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[F:25])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:26][C:27]1[CH:28]=[C:29]([S:33]([Cl:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[ClH:36].[F:25][C@H:13]1[C@H:12]([O:11][C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([NH:1][S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[CH:28]=3)(=[O:35])=[O:34])[CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cc(N)cc3ccoc23)[C@H](F)C1
Product: Cc1cccc(S(=O)(=O)Nc2cc(O[C@@H]3CCNC[C@H]3F)c3occc3c2)c1
Product: Cl

Procedure:
The title compound was prepared according to the procedure described for Example 84 starting from tert-butyl trans-4-[(5-amino-1-benzofuran-7-yl)oxy]-3-fluoropiperidine-1-carboxylate (Intermediate 53) and 3-methylbenzenesulfonyl chloride. Yield: 47 mg (27%), HPLC purity=100%, m/z=405 (M+H)+, 1H NMR (270 MHz, methanol-d4) δ ppm 2.12-2.34 (m, 2H) 2.28-2.34 (m, 3H) 3.15-3.57 (m, 3H) 3.64-3.78 (m, 1H) 4.73-4.97 (m, 1H) 4.98-5.21 (m, 1H) 6.71-6.79 (m, 2H) 7.25-7.57 (m, 4H) 7.70-7.74 (m, 1H).