Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:4][CH2:3][CH2:2]1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:4]1[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3]1
Reactant: BrCCCCCBr
Reactant: O=C1NCCOc2ccccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2OCCN1CCCCCBr
Reaction time: 1 h
Yield: 65 %

Procedure:
In 20 ml of dimethylformamide (DMF) was dissolved 100 mg of 2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one, and the solution then ice-cooled. Then, to the resulting solution were added 0.251 ml (3 equivalents) of 1,5-dibromopentane and 29.4 mg (1.2 equivalent) of a 60% sodium hydride oil dispersion, and the mixture was stirred for one hour with ice-cooling. The reaction solution was poured into a citric acid aqueous solution and extracted with ethyl acetate, and the ethyl acetate phase was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was then concentrated and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (8:2)) to give 124 mg (yield: 65.0%) of the title compound.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[NH2:11].N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(Br)cc(OCc2ccccc2)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.2 %

Procedure:
Ethylsulfonyl chloride (113 uL, 1.2 mmol) was added dropwise to a stirred solution of 3-bromo-5-phenylmethoxyaniline (284 mg, 1.0 mmol) and pyridine (247 uL, 3.1 mmol) in DCM (5 mL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 14 h, it was treated with 1N HCl (1 mL) and extracted with DCM (3×5 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 95%) in hexanes to afford the title compound (345 mg, 94%) as an amber oil that solidified upon standing. LCMS (M+H)+=371.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[N:7]([CH3:12])[C:8](=O)[CH2:9][O:10][C:5]=2[CH:4]=1.CSC.B>C1COCC1>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[N:7]([CH3:12])[CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)OCC(=O)N2C
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)OCCN2C
Yield: 9.2 %

Procedure:
7-Methoxy-4-methyl-4H-benzo[1,4]oxazin-3-one (13.07 g, 0.68 mol) was added to 100 mL dry THF, and the reaction mixture was refluxed under nitrogen. Borane-dimethyl sulfide (13.6 mL, 0.136 mol) was added dropwise over one hour, and the reaction mixture was allowed to reflux for two hours. The reaction mixture was cooled and then quenched by addition of 50 mL of 10% aqueous HCl. Precipitate was removed by filtration, and the liquid was concentrated under reduced pressure to give 11.17 g of 7-Methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine. (M+H)=180.
Reaction SMILES: C([C:5]1[CH:6]=[C:7](C(C)(C)C)[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)(C)(C)C.CC1C=CC=CC=1C>O>[O:12]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:15][C:9]=2[CH2:10][C:11]1=[O:13]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1Cc2ccccc2O1

Procedure:
To a solution of 262.3 g (1.00 mol) of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (compound (201), Table 2, Example la) in 500 ml (4.05 mol) of o-xylene are added 40 g of Fulcat 22B and the mixture is refluxed for 1.5 hours on a water separator. The Fulcat 22B catalyst is then removed by filtration and excess p-xylene is removed by distillation on a vacuum rotary evaporator. Crystallisation of the residue from 500 ml of methanol yields 244 g (69%) of 3-(3,4-dimethylphenyl)-5,7-di-tert-butyl)-3H-benzofuran-2-one, m.p. 130-132° C. (compound (103), Table 1), which additionally contains c. 1.3% of the structural isomer [3-(2,3-dimethylphenyl)-5,7-di-tert-butyl-3H-benzofuran-2-one, compound (103A)]. The mother liquor yields a further 42.4 g of product which, according to GC-MS analysis, consists of 12.3% of the compound (103) and 87.7% of the isomeric compound (103A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH2:38]([O:37][C:35](=[O:36])[C:27]1[CH:28]=[C:29]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:24])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)[C:11]([F:13])([F:14])[F:12])[CH:4]=2)[CH:30]=[CH:31][C:26]=1[F:25])[CH3:39]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(Cl)c(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c2)ccc1F

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 189, step 5) was reacted with 4-fluoro-3-ethoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless foam. MS (m/e)=528.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([OH:14])[C:8]=1[F:15])=O>C1COCC1>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:16][C:3]=1[CH2:4][NH:6][C:7]1[C:8]([F:15])=[C:9]([OH:14])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: O=C(Nc1c(F)ccc(O)c1F)c1cc(-c2cccc(F)c2)ccc1Cl
Solvent: C1CCOC1
Product: Oc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2Cl)c1F
Temperature: 60 °C
Yield: 103.5 %

Procedure:
To a solution of 2-chloro-N-(2,6-difluoro-3-hydroxy-phenyl)-5-(3-fluorophenyl)benzamide (150 mg, 0.34 mmol, 1.0 eq) in THF (3 mL) was added a solution of BH3 (1M in THF, 1.72 mL, 1.72 mmol, 5.0 eq). The reaction was heated at 60° C. for 3 h, then quenched by addition of 1M HCl. The aqueous layer was extracted with EtOAc and the organic extract was washed with water and brine, dried (Na2SO4) filtered and evaporated in vacuo. The residue obtained was purified by flash chromatography (petroleum ether:EtOAc, 100:1 to 30:1) to give the title compound as a colourless oil (128 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:34]([C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)(=[O:36])=[O:35])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccc(F)cc2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and 4-fluorobenzenesulfonyl chloride (68 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give N-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-fluoro-benzenesulfonamide LC/MS m/e obsd. (ESI+) [(M+H)+] 445.2.
Reaction SMILES: CS(O[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.CCOCC>[N:18]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)CCC(OS(C)(=O)=O)C2
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC(N=[N+]=[N-])C2

Procedure:
8.0 g (31 mmol) of 2-methanesulfonyloxy-6-methoxytetralin and 2.6 g (40 mmol) of sodium azide were heated for 3 hours at 90° C. in 100 ml of DMF. After the mixture had been cooled, it was diluted with ether, washed with water and saturated NaCl solution, dried and concentrated in vacuo. This gave 6 g (95% of theory) of a colorless oil which was further reacted directly.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:26][C:27]1[CH:31]=[C:30]([NH:32][NH2:33])[S:29][N:28]=1>>[CH3:26][C:27]1[CH:31]=[C:30]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:33]2)[S:29][N:28]=1
Reactant: Cc1cc(NN)sn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: Cc1cc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)sn1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and (3-methyl-isothiazol-5-yl)-hydrazine according to the method described for example 43. MS: M=420.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[CH:14]=[O:15]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:19][C:18]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=2[F:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: Clc1ccc(CBr)cc1
Product: O=Cc1ccc(OCc2ccc(Cl)cc2)c(F)c1

Procedure:
Additional aldehydes were prepared using the protocol of Scheme 62, replacing either 4-chlorobenzyl bromide 557 with a suitable alkylating agent, and/or 3-fluoro-4-hydroxy-benzaldehyde 598 with a suitable aldehyde. The following table indicates the alkylating agent (column 1) and the starting aldehyde (column 2) used to afford the aldehyde (column 3) synthesized following this protocol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([O:12][CH3:13])[C:3]=1[O:14]COC.Cl>CO>[Br:1][C:2]1[C:3]([OH:14])=[C:4]([O:12][CH3:13])[C:5]([O:8][CH:9]([F:10])[F:11])=[CH:6][CH:7]=1
Reactant: COCOc1c(Br)ccc(OC(F)F)c1OC
Agent: Cl
Solvent: CO
Product: COc1c(OC(F)F)ccc(Br)c1O
Temperature: 50 °C
Yield: 93.2 %

Procedure:
To a stirring solution of 1-bromo-4-(difluoromethoxy)-3-methoxy-2-(methoxymethoxy)benzene (1 g, 3.19 mmol) in methanol (15 mL) was added concentrated hydrochloride (2 mL) and the reaction mixture was heated to 50° C. for 1 h. The reaction mixture was cooled to RT, concentrated under reduced pressure and the obtained residue was basified with sodium bicarbonate solution and extracted with dichloromethane (3×). The combined dichloromethane layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford 6-Bromo-3-(difluoromethoxy)-2-methoxyphenol as a solid (800 mg, 93%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([Cl:13])[N:5]=1.[CH3:14]I.O>O1CCCC1>[Cl:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH3:14])=[C:6]([Cl:13])[N:5]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cnc2c(Cl)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
Sodium hydride (60% in mineral oil, 2.53 g, 63.5 mmol) was added to an ice-cooled solution of 2,6-dichloropurine (10.0 g, 52.9 mmol) in tetrahydrofuran (75 mL) and the mixture was stirred for 30 min. Methyl iodide (3.29 mL, 52.9 mmol) was added drop-wise and the reaction mixture was stirred over night. Water was added and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. Dichloromethane was added and undissolved material was collected by filtration. The crystalline compound turned out to be 2,6-dichloro-7-methyl-7H-purine (1.19 g, 11%) The filtrate was concentrated in vacuo and purified by flash chromatography (ethyl acetate/hepatane) to give 2,6-dichloro-9-methyl-9H-purine (3.0 g, 28%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:9]C(=O)C(C)(C)C)=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:2]>Cl>[NH2:9][C:4]1[C:3]([CH:1]=[O:2])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(C)(C)C(=O)Nc1ncccc1C=O
Agent: Cl
Product: Nc1ncccc1C=O
Temperature: 25 °C
Yield: 87.8 %

Procedure:
N-(3-Formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (9.68 g) was dissolved in 3 N hydrochloric acid (140 ml), and the solution was stirred under reflux overnight. The reaction solution was cooled to room temperature, was then washed with diethyl ether, and was neutralized with potassium carbonate powder. Diethyl ether was added thereto, and the mixture was extracted. The diethyl ether layer was dried over potassium carbonate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-chloroform to give 2-amino-pyridine-3-carbaldehyde (5.03 g, yield 88%).
Reaction SMILES: C([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[N:9]=1)(=O)C.[ClH:31]>CO>[ClH:31].[ClH:31].[ClH:31].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[N:9]=1
Reactant: CC(=O)Nc1nc(CCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Agent: Cl
Solvent: CO
Product: Nc1nc(CCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1

Procedure:
A mixture of 2-acetamido-4-[2-(4-benzhydrylpiperazin-1-yl)ethyl]thiazole (3.75 g), methanol (26 ml) and conc. hydrochloric acid (13 ml) was refluxed under heating for 2.5 hours. After concentration of the reaction mixture, the concentrate was recrystallized from methanol to obtain white crystals (3.4 g) of 2-amino-4-[2-(4-benzhydrylpiperazin-1-yl)ethyl]thiazole trihydrochloride, mp 188°-190° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][CH:4]=1.[H][H]>[Ni].CO>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CSc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: CSc1ccc(N)cc1
Yield: 92.7 %

Procedure:
A suspension of 1-(methylsulfanyl)-4-nitrobenzene (10.5 g, 0.062 mol) and Raney nickel (5 g) in methanol (250 ml) was hydrogenated in a round flask equipped with a balloon filled with hydrogen at room temperature for 16 hours. The resulting mixture was filtered and concentrated in vacuo to afford 8.0 g of 4-(methylsulfanyl)aniline as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC=O
Reactant: COc1cccc(N)c1
Product: CCCCNc1cccc(OC)c1
Yield: 96.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 3-methoxyaniline (460 μl, 4.06 mmol) and butyraldehyde (360 μL, 4.06 mmol) were converted to the title compound (700 mg, 88%). 1H NMR (CDCl3) δ 7.36-7.20 (m, 1H), 6.56-6.32 (m, 3H), 4.02-3.95 (m, 3H), 3.87 (br s, 1H), 3.30 (t, J=7.0 Hz, 2H), 1.86-1.71 (m, 2H), 1.71-1.58 (m, 2H), 1.19-1.10 (m, 3H); MS(ESI+) m/z 179.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]2[CH:41]=[CH:42][CH:43]=[CH:44][C:26]=2[C:25]2[CH2:45][CH2:46][CH:47]=[CH:48][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:27]2[CH:41]=[CH:42][CH:43]=[CH:44][C:26]=2[C:25]2[CH:45]=[CH:46][CH:47]=[CH:48][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:8]
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Reactant: CC(C)[C@H](N)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2C2=C1C=CCC2
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@@H](O)c1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-U), the title compound was prepared. The product was purified by chromatography (silica, 1-2% MeOH/CHCl3).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(OC(=O)C)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: CCCCCCC(O)C(=O)O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCC(O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of a commercially available racemic 2-hydroxyoctanoic acid mixture (1.00 g, 6.2 mmol.) in HPLC-grade ethylacetate (30 ml), there are added in succession benzyl bromide (2.22 ml; 18.7 mmol.), triethylamine (2.6 ml, 18.7 mmol.) and tetrabutylammonium iodide (1.15 g; 3.12 mmol.). The solution is stirred for 18 hours at room temperature and the solvent is thereafter evaporated. The residue is taken up into ether and the organic layer is then washed with a saturated solution of NaHCO3 and H2O (2×). The organic layer is dried over MgSO4, filtered and evaporated to yield crude benzyl 2-hydroxyoctanoate (Rf=0.57 in a 3/1 petroleum ether/EtOAc mixture; phosphomolybdinium compound and U.V. color development agent)
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][C:38](=[O:41])[NH:37][CH2:36]1>>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:35]4[CH2:40][CH2:39][C:38](=[O:41])[NH:37][CH2:36]4)=[CH:29][CH:28]=3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: O=C1CCNCN1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Product: Nc1ncnn2c(-c3ccc(CN4CCC(=O)NC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 4.5 %

Procedure:
Using a procedure similar to that of Example 282, step 2, with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and tetrahydro-pyrimidin-4-one as starting materials, 14 mg (4.5%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.60 (s, 2 H), 3.20 (t, 2 H), 2.95 (s, 2 H), 2.60 (t, 2 H); ES-MS m/z 529.29 [M+H]+, HPLC RT (min) 2.24.
Reaction SMILES: [C:1]1([C@@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1.O>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[N:9][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: O
Solvent: c1ccccc1
Product: C[C@H](N=C1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.9 %

Procedure:
To a solution of (S)-1-phenylethanamine (1.921 g, 15.85 mmol) in benzene (8.81 ml) were added molecular sieves in water and 1-benzylpiperidin-4-one (2.50 g, 13.21 mmol). The reaction was stirred at room temperature for 5 hrs. The product mixture was filtered and concentrated under reduced pressure to give a yellow oil, which was standing under vacuum at 45° C. for 14 hrs to remove the residual reactant, yielding (S)—N-(1-benzylpiperidin-4-ylidene)-1-phenylethanamine (3.24 g, 11.08 mmol, 84.0% yield) as a yellow oil. 1H NMR (400 MHz, methanol-d4) δ 7.33-7.25 (m, 10H), 4.81-4.76 (m, 1H), 3.54 (s, 2H), 2.72-2.33 (m, 8H), 1.47 (d, J=6.6 Hz, 3H). LCMS (method K) m/z 291.3 ([M+H]+).
Reaction SMILES: [OH-].[K+].[CH:3]([NH:6][C:7]([C:9]1[S:13][N:12]=[C:11]([CH2:14][CH3:15])[C:10]=1[C:16]([O:18]C)=[O:17])=[O:8])([CH3:5])[CH3:4]>O.C(O)C>[CH:3]([NH:6][C:7]([C:9]1[S:13][N:12]=[C:11]([CH2:14][CH3:15])[C:10]=1[C:16]([OH:18])=[O:17])=[O:8])([CH3:4])[CH3:5]
Reactant: CCc1nsc(C(=O)NC(C)C)c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1nsc(C(=O)NC(C)C)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
2.8 g of KOH in 30 ml of water are added to 11 g of the ester from Example 5 in 50 ml of ethanol, and the mixture is stirred overnight at room temperature. It is diluted with 150 ml of water and extracted with ether, and the aqueous phase is acidified with concentrated hydrochloric acid. Extraction by shaking with dichloromethane and evaporation give 10 g of 5-isopropylaminocarbonyl-3-ethylisothiazole-4-carboxylic acid of melting point 138°-140° C. (compound 3006).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:23]3[CH:27]=[C:26]([CH:28]4OCC[O:29]4)[S:25][CH:24]=3)[S:22][C:13]=12.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:23]3[CH:27]=[C:26]([CH:28]=[O:29])[S:25][CH:24]=3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4csc(C5OCCO5)c4)sc23)c(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4csc(C=O)c4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To the suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-dioxolan-2-yl)thien-3-yl]thieno[3,2-b]pyridine-6-carbonitrile (337 mg, 0.67 mmol) in 10 mL of tetrahydrofuran is added 5 mL of 2N hydrochloric acid. The mixture is stirred at room temperature, overnight. The mixture is slowly poured into 30 mL of saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane to provide 271 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formylthien-3-yl)thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 259–261° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 7.38 (s, 1H), 7.76 (s, 1H), 7.93 (s, 1H), 8.42 (s, 1H), 8.50 (s, 1H), 8.63 (s, 1H), 9.76 (s, 1H), 9.98 (s, 1H); MS 458.1 (M−H)−.