Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][O:9][C:8]([NH:12][C@H:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:11]3[CH2:10][O:9][C:8]([NH:12][C@H:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH2:15][CH2:14]4)=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: Brc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(-c2cccc3c2COC(N[C@@H]2CCc4ccccc42)=N3)cc1
Temperature: 80 °C
Yield: 91.5 %

Procedure:
A stirred mixture of (5-bromo-4H-benzo[d][1,3]oxazin-2-yl) -(R)-indan-1-yl-amine (Example 10) (171.6 mg, 0.5 mmol), 4-fluorophenyl-boronic acid (84 mg, 0.6 mmol), 1M sodium carbonate solution (1.25 ml, 1.25 mmol), tetarkis(triphenylphosphine)palladium (17.3 mg, 0.015 mmol) in 1,2-dimethoxy-ethane (2.5 ml) was heated at 80° C. for 17 h. The reaction mixture was poured into water (20 ml), extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography (ethyl acetate/heptane) on silica gel yielded the title compound as white foam (164 mg, 92%). MS (ISP) m/e=359.1 [(M+H)+].
Reaction SMILES: F[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:24][NH:25][CH3:26]>CS(C)=O.O>[CH3:24][N:25]([CH3:26])[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: CNC
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1F
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1N(C)C
Temperature: 60 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
A solution of rac-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 156; 32.0 mg, 0.103 mmol) and dimethylamine (2.0M in THF; 0.155 mL, 0.309 mmol) in DMSO (0.8 mL) was stirred under argon in a sealed microwave flask at 25° C. for 10 min, then at 60° C. for 18 h. Additional dimethylamine (2.0M in THF; 0.155 mL, 0.309 mmol) was added, and the resulting mixture was stirred under argon in a sealed microwave flask at 60° C. for 4.5 h. The reaction was cooled to 25° C. and diluted with water (10 mL). The precipitated solid was collected by vacuum filtration, washed with water (2×5 mL), and dried in vacuo to provide rac-2-(3-(dimethylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (22.7 mg, 0.068 mmol, 66% yield) as a yellow-orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (1H, br. s.), 7.96 (1H, dd, J=7.5, 1.1 Hz), 7.66 (1H, dd, J=8.1, 0.9 Hz), 7.47 (1H, t, J=7.8 Hz), 7.08 (1H, d, J=2.2 Hz), 6.99 (1H, br. s.), 3.40-3.49 (1H, m), 3.13-3.15 (6H, m), 3.06-3.18 (2H, m), 2.71 (3H, s), 1.30 (3H, d, J=6.5 Hz). m/z (ESI, +ve) 336.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14].O.C1C=C(Cl)C=C(C(OO)=O)C=1>CO>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:14][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: O=S(=O)(O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 96.4 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of methanol in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature without irradiation by lamps. After completion, methanol was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 16.9 g of 1-benzyl-3,4-epoxypyrrolidine (yield 96.7%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1ccc(O)cc1
Reaction time: 24 h
Yield: 80 %

Procedure:
A solution of 17 gm (0.1 mole) of 3-(4-hydroxyphenyl) propionic acid in 500 ml methanol and 2 ml concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3A molecular sieves. The solution was heated to reflux for 72 hours and the sieves were exchanged at 24 hour intervals. The reaction medium was then evaporated to an oil which was dissolved in 100 ml toluene and extracted with 3×100 ml water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to provide 15 gm (80%) of a clear oil. The NMR spectrum was consistent with the assigned structure and this material was utilized directly in the next reaction step.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([O:25][CH3:26])[C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[NH4+:28]>C(Cl)Cl>[C:1]([N:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([O:25][CH3:26])[C:19]([S:21](=[O:23])(=[O:22])[NH2:28])=[CH:20][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [NH4+]
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2c1ccccc1
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc2c(cc1S(N)(=O)=O)CCN(C(C)=O)CC2c1ccccc1

Procedure:
3-Acetyl-7-chlorosulfonyl-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (3.9 g, 0.01 m) is dissolved in methylene chloride (50 ml) and added to concentrated ammonium hydroxide (15 ml), then stirred and filtered to give 3-acetyl-8-methoxy-1-phenyl-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:12]([O:14]C)=[O:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].Cl>C1COCC1.O>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COC(=O)c1cccc2c1NC(C)(C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCc2cccc(C(=O)O)c2N1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2,2-dimethyl-1,2,3,4-tetrahydroquinoline-8-carboxylate (0.138 g, 0.629 mmol) in THF (5 mL) and H2O (5 mL) was added a 1N aqueous solution of sodium hydroxide (1.88 mL, 1.88 mmol). After stirring at 50° C. overnight the reaction mixture was acidified to pH 2 using 1N aqueous HCl, extracted with ethyl acetate (three times), dried over MgSO4 and concentrated under vacuum to afford the desired compound that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[O:8][C:7]=2[CH:18]=1.[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)#[N:20]>Cl[Ti](Cl)(Cl)Cl.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:25]([C:24]3[CH:28]=[CH:29][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)=[O:26])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[O:8][C:7]=2[CH:18]=1
Reactant: COc1ccc2cc(-c3ccc(C)cc3)oc2c1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(C#N)cc3)c(-c3ccc(C)cc3)oc2c1
Reaction time: 4 h

Procedure:
One gram (4.2 mmol) of 6-Methoxy-2-(4methylphenyl)benzo[b]furan was dissolved 25 mL of dichloromethane and 830 mg (5.0 mmol) of 4-cyanobenzoyl chloride was added. The reaction was stirred and kept under a nitrogen atmosphere. 2.75 mL (25 mmol) of TiCl4 was slowly added to the reaction mixture. The reaction was allowed to proceed for four hours and quenched by the addition of 5 mL of methanol (MeOH). The solvents were removed by evaporation and the crude material was chromatographed on a silica gel column eluted with hexane-EtOAc (9:1). The desired fractions were determined by tlc and combined and evaporated to a solid. The resulting product was crystallized from diethyl ether (Et2O). This yielded 325 mg of the title compound as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:22][C:7]1[N:6]=[CH:5][C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:3][C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(Cl)c2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCN(c2cnc(Br)c(Cl)c2)CC1
Reaction time: 1 h

Procedure:
A mixture of 1-(5-chloro-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine (2.34 g, 7.5 mmol), N-bromosuccinimide (1.34 g, 7.5 mmol) and acetonitrile (75 ml) was stirred for 60 minutes. The crude mixture was evaporated and purified by chromatography on silica gel using ethyl acetate:petroleum (2:1) as solvent. Yield 2.5 g, 85%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[CH:11]([NH:14][C:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10])=[O:16])([CH3:13])[CH3:12]
Reactant: CC(C)N=C=O
Reactant: O=C1Cc2ccccc2N1
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a stirred suspension of 5.0 g (37.6 mmole) of 2-oxindole in 50 ml of toluene was added 8.0 g (94.0 mmole) of isopropyl isocyanate, and the mixture was heated under reflux for 6 hours. The reaction mixture was allowed to cool and then it was stirred at room temperature overnight. The solvent was removed by evaporation in vacuo, and the residue was dissolved in hot cyclohexane. The solution was allowed to cool and the solid was collected by filtration, giving 7.0 g of the title compound, mp 84°-85.5° C., as pink crystals.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11]C)=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:31])[N:5]([C@@H:14]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:6]2=[O:13].I[Si](C)(C)C>C(Cl)Cl.[Cl-].[Na+].O>[NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:31])[N:5]([C@@H:14]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:6]2=[O:13]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3ccc(OC)c(N)c3C2=O)ccc1OC
Agent: C[Si](C)(C)I
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3ccc(O)c(N)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Amino-4-methoxy-phthalic anhydride is prepared according to a procedure based on Rudolf Grewe (Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1938), 71B 907-11). A stirred mixture of 3-amino-4-methoxy-phthalic anhydride (1 mmol) and (S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (1 mmol) in acetic acid is heated to reflux overnight. The solvent is removed in vacuo. The residue is extracted with water and ethyl acetate. The organic layer is dried over MgSO4. The solvent is removed in vacuo to give the crude (S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-5-methoxy-isoindole-1,3-dione. The product is purified by column chromatography or recrystallization. To a stirred solution of (S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-5-methoxy-isoindole-1,3-dione (0.5 mmol) in anhydrous CH2Cl2, is added iodotrimethylsilane (3 mmol). The mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with brine and is extracted with CH2Cl2. The solvent is removed in vacuo to afford crude (S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-5-hydroxy-isoindole-1,3-dione. The product is purified by column chromatography or recrystallization.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](OCC)OCC)=[CH:4][C:3]=1[F:17].C(=O)(O)O.[NH2:22][NH:23][C:24]([NH2:26])=[NH:25].[OH-].[K+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:22]=[N:23][C:24]([NH2:26])=[N:25][CH:9]=2)=[CH:4][C:3]=1[F:17]
Reactant: CCOC(OCC)C(=O)c1ccc(Br)c(F)c1
Reactant: N=C(N)NN
Agent: O=C(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Temperature: 110 °C

Procedure:
A mixture of 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone (Step 4, 15.2 g, 50 mmol), aminoguanidine bicarbonate (10.2 g, 75 mmol) and potassium hydroxide (6.6 g, 100 mmol) in ethanol (200 mL) and water (4 mL) was refluxed overnight. The solvent was evaporated under reduced pressure and the residue was washed with acetonitrile and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), washed with water, brine, and concentrated under reduced pressure. The residue was dissolved in ethanol (50 mL). To the solution was added 0.2N hydrochloric acid (50 mL). The resultant mixture was heated to 110° C. for 8 h, and cooled with an ice-water bath. The precipitate that formed was collected by filtration and washed with isopropanol to give the desired product. (5.5 g, 41%) LCMS: (M+H)=286.8/288.8. 1H-NMR (400 MHz, CDCl3): 8.60 (s, 1H), 7.79 (dd, J=8.6, 2.0 Hz, 1H), 7.68 (dd, J=8.3, 7.0 Hz, 1H), 7.61 (dd, J=8.3, 2.0 Hz, 1H), 5.43 (s, 2H).
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1.FC1C=CC(S(F)(F)(F)(F)F)=CC=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38](S(F)(F)(F)(F)F)=[CH:37][CH:36]=1.FS(F)(F)(F)(F)C1C=CC(O)=CC=1>CO>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:11]2[CH:12]=[CH:13][C:8]([S:7]([F:19])([F:18])([F:17])([F:16])[F:6])=[CH:9][CH:10]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: F[B-](F)(F)F
Agent: Fc1ccc(S(F)(F)(F)(F)F)cc1
Agent: Oc1ccc(S(F)(F)(F)(F)F)cc1
Solvent: CO
Product: COc1ccc(-c2ccc(S(F)(F)(F)(F)F)cc2)cc1
Reaction time: 312 h

Procedure:
In Methanol: Diazonium salt 1 (22.5 mg, 0.0314 mmol) was dissolved in methanol (0.82 mL). After 13 d stirring at room temp. a portion of the solution was diluted with CDCl3 and analyzed by NMR, which indicated the formation of 1-fluoro-4-(pentafluorosulfanyl)benzene 30, (Umemoto, et al., Beilstein J. Org. Chem. 2012, 8, 461-471) 1-methoxy-4-(pentafluorosulfanyl)-benzene, (Beier, et al., Org. Lett. 2011, 13, 1466-1469) and 4-(pentafluorosulfanyl)phenol (Beier, et al., Org. Lett. 2011, 13, 1466-1469).
Reaction SMILES: [OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(O)C>ClCCl>[OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(C)[C@H](O)C(=O)O
Reactant: COc1ccc(CCl)cc1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(COC(=O)[C@@H](O)C(C)C)cc1

Procedure:
2-hydroxy-3-methyl-(S)-(+)-butyric acid (1.77 g) was esterified by alkylation with 4-methoxybenzyl chloride by the method described in Example A-I-1, step a. The title compound (3.10 g) was obtained after silica gel column chromatography (0, 1, 2% ethanol in dichloromethane). Rf (2%MeOH/CHCl3) 0.50.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][CH2:4][NH:3]1.Cl[C:14]1[CH:23]=[C:22]([Cl:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:25])[CH:20]=2)[N:15]=1>>[Cl:24][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:25])[CH:20]=2)[N:15]=[C:14]([N:3]2[CH:2]([CH3:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][CH2:5][CH2:4]2)[CH:23]=1
Reactant: CC1NCCSc2ccccc21
Reactant: Cc1ccc2nc(Cl)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCSc4ccccc4C3C)cc(Cl)c2c1
Temperature: 170 °C
Reaction time: 5 h
Yield: 28.3 %

Procedure:
A mixture of 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.0 g, 5.58 mmol) and 2,4-dichloro-6-methylquinoline (1.7 g, 8.02 mmol) was heated with stirring in a 2 mL of microwave process vial for 5 hours at 170° C. under microwave irradiation. The solvent was removed by concentration in vacuo. The residue was purified by flash column chromatography to give 560 mg of the mixture of 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 4-(4-chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH2:14][CH2:15]I)[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]#[N:20])[O:8][C@H:7]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:6]=2[CH:31]=1.[CH3:32][C:33]1[NH:34][CH:35]=[CH:36][N:37]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][N:34]3[CH:35]=[CH:36][N:37]=[C:33]3[CH3:32])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]#[N:20])[O:8][C@H:7]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:6]=2[CH:31]=1
Reactant: Cc1ncc[nH]1
Reactant: N#CC[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CCCCI)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nccn1CCCCN1C(=O)[C@@H](CC#N)O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.3 %

Procedure:
Trans-7-chloro-5-(1 -naphthyl)-1 -(4-iodobutyl)-2-oxo-1,2,3,5-tetrahydro-4,1 -benzoxazepine-3-acetonitrile (575 mg, 1.06 mmol), 2-methylimidazole (87 mg, 1.06 mmol) and potassium carbonate (146 mg, 1.06 mmol) were dissolved in DMF (5 ml) and the resulting solution stirred at 25° C. for 72 hours. Ethyl acetate was added and the solution washed with water (4×). The organic layer was dried (MgSO4), concentrated under reduced pressure and purified by flash column chromatography (ethyl acetate/diethylamine 95:5) to give the title compound (250 mg, 47%) as a colorless foam.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][O:8]CC)(=[O:5])[OH:4])[CH3:2].[OH-:11].[Na+].C>O>[CH2:1]([P:3]([OH:4])([CH2:6][C:7]([OH:8])=[O:11])=[O:5])[CH3:2]
Reactant: CCOCCP(=O)(O)CC
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CC(=O)O
Temperature: 70 °C
Yield: 78 %

Procedure:
16.6 g (0.1 mol) of ethyl(2-ethoxyethyl)phosphinic acid (produced as in Example 8) are dissolved in 150 ml of water and adjusted to pH 9 with 2N NaOH solution. Then, 0.45 g of charcoal with 5% Pt and 1% Bi is added, the suspension is heated to 70° C. and air is passed through the suspension at 10 l/h. All the while, the pH of the suspension is maintained at pH=9 by adding 2N NaOH solution. After the reaction is ended, the reaction solution is filtered to remove the catalyst, which is washed, and made acidic with hydrochloric acid and the water is distilled off in vacua. The residue is taken up in tetrahydrofuran and extracted. The insoluble salts are filtered off to leave 11.9 g (78% of theory) of 2-(ethylhydroxyphosphinyl)acetic acid as a colorless solid material.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:24])[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.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:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([C:18]2[CH:19]=[CH:20][C:15]([CH3:24])=[CH:16][CH:17]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
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: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Yield: 79.5 %

Procedure:
To a mixture of tert-butyl-4-bromobenzoate (40 g, 0.15 mol), 4-tolylboronic acid (23.3 g, 0.17 mol) and sodium carbonate (150 g) in toluene (350 mL) and water (350 mL) was added tetrakis(triphenylphosphine)palladium(0) (8.7 g, 0.007 mol) and the reaction mixture was refluxed for 10 h under nitrogen atmosphere. The organic layer was separated, washed with water, dried and concentrated to give tert-butyl-4-(4-tolyl)benzoate (32 g, 77%).
Reaction SMILES: C([O:5][C:6](=[O:40])[C@@H:7]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:8][NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21]C(OC(C)(C)C)=O)=[CH:13][CH:12]=1)(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[NH2:21][CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:30][S:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[C:6]([OH:40])=[O:5])=[O:29])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCOc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Reaction time: 0.17 h

Procedure:
8-5 (497 mg, 1.04 mmol) in 5 mL CH2Cl2 was treated with 5 mL TFA at 0° for 30 min then RT for 10 min. Concentration provided 9-1 as a yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([C:18]3[CH:23]=[C:22]([C:24]4[O:25][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:27][N:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:33])[C:7]2=[O:34])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:40]>ClCCl.C(OCC)(=O)C>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:40])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([C:18]3[CH:23]=[C:22]([C:24]4[O:25][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:27][N:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:33])[C:7]2=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2cc(-c3cc(-c4nnc(CC(C)C)o4)ccc3C)c(=O)n(C3CCCC3)c2n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(-c2nnc(CC(C)C)o2)cc1-c1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 152.6 %

Procedure:
To a solution of 8-cyclopentyl-6-{5-(5-isobutyl-[1,3,4]oxadiazol-2-yl)-2-methyl-phenyl}-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (40.0 mg, 0.08 mmol) in dichloromethane (3 mL) at 0° C. was added 3-chloroperoxybenzoic acid (0.04 g, 0.19 mmol). The mixture was stirred at 0° C. for 1 hour, then was diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure to give 8-cyclopentyl-6-{5-(5-isobutyl-[1,3,4]-oxadiazol-2-yl)-2-methyl-phenyl}-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.06 g). The crude product was used in the next step without further purification.