Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14](Br)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:12]=1)=[O:10].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32]>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([O:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Cl:25])=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:12]=1)=[O:10]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Reactant: Oc1ccccc1Cl
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Oc2ccccc2Cl)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 36 c, using 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide, and chlorophenol (commercially available) as starting materials to give the title compound as a white solid. mp.: 154-155° C., MS (ISP): 458.3, 460.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.[CH2:41](Cl)Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:41][N:32]1[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[O:40]
Reactant: ClCCl
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 0 °C

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester (4.9 g) was dissolved in 200 mL dry DCM and stirred on 0° C. bath. 100 mL 4N HCL in dioxane was added and the mixture stirred to rt over 3 h. The solvents were evaporated and the residue was evaporated from diethyl ether 4 times. 4 g of the residue was dissolved in 250 mL dry dioxane and 462 mg paraformaldehyde was added while stirring. Then 62.5 mL trifluoroacetic acid was added and the mixture was stirred 1.5 h. The solvents were then evaporated and the residue was dissolved in 250 mL EtOAc and 250 mL saturated aqueous NaHCO3, and 4.2 g di-t-butyl dicarbonate was added and stirred 18 h at rt. The layers were then separated and the organic layer was washed with brine, dried with Na2SO4, and evaporated. The residue was purified by silica gel flash chromatography (9:1 to 7:3 hexanes/EtOAc) to give 3.25 g after drying under vacuum. 1H NMR (400 MHz, acetone-d6): 7.72 (d, 1H), 7.61 (d, 1H), 7.51-7.42 (m, 3H), 7.12-7.07 (m, 2H), 0.680-6.70 (m, 2H), 5.20 (s, 2H), 5.13-5.07 (m, 1H), 5.02 and 4.76 (m, 1H), 4.66-4.52 (dd, 1H), 4.42 (d, 1H), 4.36-4.30 (m, 1H), 4.01 (m, 1H), 3.64 and 3.60 (s, 3H), 3.18-3.00 (m, 2H), 1.49 and 1.43 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.[C:14]([CH2:16][C:17]([OH:19])=[O:18])#[N:15].N1C=CC=CC=1>C1C=CC=CC=1>[C:14]([C:16](=[CH:8][C:7]1[C:2]([Br:1])=[CH:3][CH:4]=[C:5]([O:12][CH3:13])[C:6]=1[O:10][CH3:11])[C:17]([OH:19])=[O:18])#[N:15]
Reactant: N#CCC(=O)O
Reactant: COc1ccc(Br)c(C=O)c1OC
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1ccc(Br)c(C=C(C#N)C(=O)O)c1OC
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of 6-bromo-2,3-dimethoxybenzaldehyde (48.4 g, 0.20 mole), NH4OAc (1.93 g, 0.025 mole), cyanoacetic acid (0.186 mole, 15.8 g), pyridine (42 mL), and benzene (193 mL) was stirred at reflux for 2 hours using a Dean-Stark trap for water removal. Upon cooling to room temperature a solid was filtered and washed with hexane. The solid was dissolved in 1N KOH, and was extracted with ether. The aqueous layer was acidified with 10% HCl and was extracted with CH2Cl2. The combined CH2Cl2 layers were washed with water, saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated to yield 41.7 g yellow solid, (67%); mp 130°-2°; M+ 311.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:44])[NH:6][C:7]2[CH:42]=[CH:41][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]=[CH:23][N:24]([CH2:26][CH2:27][N:28]6[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]6)[CH:25]=5)[S:20][C:13]=34)=[C:9]([F:43])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:42]=[CH:41][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]=[CH:23][N:24]([CH2:26][CH2:27][N:28]6[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]6)[CH:25]=5)[S:20][C:13]=34)=[C:9]([F:43])[CH:8]=2)=[O:44])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2cnc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4cn(CCN5CCNCC5)cn4)sc23)c(F)c1)NC1CC1
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a solution of 307 (1.4 g, 2.25 mmol) in DCM (30 ml) was added TEA (2 mL) and the reaction mixture was stirred for 1 h. More TFA (3 mL) was added and the reaction mixture was stirred for an additional 3 h then concentrated, diluted with water and 1M NaOH to pH 11. The solid was collected by filtration, rinsed with water and dried. The residue was purified by Biotage (SNAP 80 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 35/65 over 30 CV), to afford the title compound 308 (870 mg, 1.67 mmol, 74% yield) as a beige solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][NH:8]1)=[O:6])[CH3:3].[CH2:13](N(CC)CC)[CH3:14].C(I)C>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][N:8]1[CH2:13][CH3:14])=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@@H]1C[C@H](O)CN1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCI
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H](O)CN1CC

Procedure:
To a suspension of 12 g of (2S,4S)-2-ethoxycarbonyl-4-hydroxy pyrrolidine hydrochloride obtained in the preceeding para. (1) in 60 ml of chloroform, were added 12.42 g of triethylamine and the combined was added with 17.22 g of ethyl iodide and heat-refluxed for 4 hours. The reaction mixture was after-treated to obtain (2S,4S)2-ethoxycarbonyl-N-ethyl-4-hydroxy pyrrolidine as an oily (product Yield 9.55 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][C:13](C)=O.C(=O)=O.C([Mg]Br)=C.[N+](C1C=CC=CC=1)([O-])=O.CC#N.C(=O)=O>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]2[C:4]=1[CH:12]=[CH:13][NH:9]2
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Agent: C=C[Mg]Br
Agent: O=C=O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CC#N
Solvent: C1CCOC1
Product: Fc1ccc(Br)c2[nH]ccc12
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromo-5-fluoronitrobenzene (4.4 g, 20 mmol) in dry THF (200 mL) under N2 was cooled to −65° C. (acetone/CO2). A solution of vinylmagnesium bromide (60 mL, 1 M, 60 mmol) in THF was added to the nitrobenzene solution as rapidly as possible maintaining the reaction temperature below −40° C. After addition of the Grignard reagent, the cooling bath was switched to a −40° C. bath (CH3CN/CO2), and the mixture was stirred at −40° C. for 30 min. The reaction mixture was quenched with sat. NH4Cl solution (500 mL) and extracted with ether (2×200 mL), then dried (brine, Na2SO4) and concentrated in vacuo. The resulting material was purified by SiO2 flash column chromatography (5:95) EtOAc/Hexanes to give 4-fluoro-7-bromoindole, as a light brown oil (2.03 g, 9.5 mmol, 54%). 1H NMR (CDCl3) δ 6.72 (m, 2H), 7.24 (m, 2H), 8.4 (br s, 1H). MS m/e 215 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:19](=O)[CH2:18][O:17][CH:16]([CH:21]=[C:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]2=3)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH:21]=[C:22]2[C:23]3[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=3[CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=3)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1COC(C=C2c3ccccc3CCc3ccccc32)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C(=C1c2ccccc2CCc2ccccc21)C1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium aluminum hydride (0.05 g) in anhydrous tetrahydrofuran (7 ml) was added a solution of 5-(4-benzyl-5-oxomorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.55 g) in anhydrous tetrahydrofuran (15 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for one hour and refluxed with stirring for 7 hours. The reaction mixture was cooled, admixed with water and extracted with ether. The ether extract was dried over anhydrous sodium sulfate and evaporated to afford 5-(4-benzylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 209°-210° C. (decomp.) (oxalate).
Reaction SMILES: [Mg].Br[CH2:3][CH3:4].[Cl:5][C:6]1[N:11]=[C:10]([Cl:12])[C:9]([F:13])=[CH:8][N:7]=1>O1CCCC1.COCCOC>[Cl:5][C:6]1[NH:7][CH:8]([CH2:3][CH3:4])[C:9]([F:13])=[C:10]([Cl:12])[N:11]=1
Reactant: CCBr
Reactant: Fc1cnc(Cl)nc1Cl
Agent: [Mg]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CCC1NC(Cl)=NC(Cl)=C1F

Procedure:
To magnesium turnings (4.27 g) in tetrahydrofuran (56 ml) was added a solution of bromoethane (19 g) in THF (19 ml) over 5 hours. To this slurry at 0° C. was added a solution of the product of part (i) (24 g) in 1,2-dimethoxyethane (70 ml) over 1 hour. The reaction was quenched at 10° C. using glacial acetic acid (10 g) to give a solution of the title compound which was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:15]=2[CH2:29][NH2:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:15]=2[CH2:29][NH:30][C:39](=[O:41])[N:20]3[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(NCc3ccc(F)cc3)c2CN)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CNC(=O)N3Cc2ccc(F)cc2)CC1
Temperature: 0 °C

Procedure:
A solution of 4-[2-aminomethyl-3-(4-fluoro-benzylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (255 mg, 0.62 mmol) in CH2Cl2 (6 ml) was cooled to 0° C. and NEt3 (0.19) ml, 1.36 mmol) and triphosgen (64 mg, 0.22 mmol) were added. After stirring at 0° C. for half an hour, the reaction mixture was allowed to warm up to room temperature and was partitioned between water and ethyl acetate. The organic layer was washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 4-[1-(4-fluoro-benzyl)-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid. (179 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([C:10]3([F:13])[CH2:12][CH2:11]3)[CH2:9][O:8]2)=[CH:4][CH:3]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]([C:10]2([F:13])[CH2:12][CH2:11]2)([OH:8])[CH2:9][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:4][CH:3]=1
Reactant: FC1(C2(Cc3ccc(Cl)cc3)CO2)CC1
Reactant: c1nc[nH]n1
Solvent: CN(C)C=O
Solvent: O
Product: OC(Cc1ccc(Cl)cc1)(Cn1cncn1)C1(F)CC1
Yield: 47.4 %

Procedure:
A solution of 3.3 g (15.7 mmol) of 2-(4-chlorobenzyl)-2-(1-fluorocyclopropyl)-oxirane in 10 ml of dimethylformamide is added dropwise to a mixture of 3.3 g (47.1 mmol) of 1,2,4-triazole end 0.35 g (3.14 mmol) of potassium tert.-butylate in 20 ml of dimethylformamide at a temperature of 80° C., while stirring. When the addition has ended, the reaction mixture is stirred for 13 hours at 80° C. The solvent is then stripped off under reduced pressure, and the remaining residue is taken up with water. The aqueous phase is extracted four times with methylene chloride. The combined organic phases are dried over sodium sulphate and then concentrated under reduced pressure. The remaining residue is chromatographed over silica over silica gel using cyclohxane:ethylacetate=2:1 as the mobile phase. Evaporation of the eluate gives 2.2 g (47% of theory) of 1-(4-chlorophenyl)-2-(1-fluorocyclopropyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol in form of a solid substance.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:12]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C.S([Cl:32])(C)(=O)=O>ClCCl.[Cl-].[Na+].O>[Cl:32][CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:12]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Cc1cccnc1Oc1cccc(CO)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cccnc1Oc1cccc(CCl)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-(3-hydroxymethylphenoxy)-3-pyridinylacetate (0.6 g) and triethylamine (0.45 ml) in dichloromethane (2 ml) was added dropwise over 20 minutes to a stirred solution of mesyl chloride (0.26 ml) in dichloromethane (6 ml) at ca. 5° C. The mixture was stirred at 5° C. for 30 minutes, warmed to room temperature and then allowed to stand over the weekend. GC analysis of an aliquot indicated complete reaction. The reaction mixture was stirred with brine for 30 minutes and then the organic layer was dried, filtered and evaporated to give methyl 2-(3-chloromethylphenoxy)-3-pyridinylacetate as a pale yellow oil (0.55 g) which was used directly.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[Br:11]Br>C(Cl)Cl>[Br:11][C:7]1[CH:8]=[CH:9][C:4]2[NH:3][C:2](=[O:10])[O:1][C:5]=2[CH:6]=1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: BrBr
Solvent: ClCCl
Product: O=c1[nH]c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 19.5 h

Procedure:
To a mixture of 3H-benzooxazol-2-one (20 g, 0.15 mol) in DCM (500 mL) was added bromine (8.34 mL, 0.16 mol). After stirring at room temperature for 19.5 h, the orange precipitate that had formed was filtered off and washed with DCM until the orange color was washed out. The filtrate was concentrated to approximately 33% of its original volume and filtered and washed as before. The combined solids weighed 28.36 g. 1H NMR indicated the product was clean albeit contained ca. 8-9% starting material meaning the true yield of product was 26.72 g, 84%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1.BrC1C=CC2OCCN3C(CN4C=CN=C4C)=C(C(N)=O)N=C3C=2C=1.N1CCCC1=O.[CH3:57][C:58]([OH:62])([C:60]#[CH:61])[CH3:59]>>[OH:62][C:58]([CH3:59])([CH3:57])[C:60]#[C:61][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1
Reactant: NC(=O)c1nc2n(c1CN1CCCC1=O)CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: O=C1CCCN1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(CN3CCCC3=O)n1CCO2
Yield: 63 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((2-oxopyrrolidin-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylimidazole with 2-pyrrolidinone) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (64 mg, 63%).
Reaction SMILES: NC1N=CN=C2N(CCC[N:27]3[C:31](=[O:32])[CH2:30][S:29][C:28]3=[O:33])N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.[CH:34]1([CH:37]=O)[CH2:36][CH2:35]1.N1CCCCC1>C(O)C>[CH:34]1([CH:37]=[C:30]2[S:29][C:28](=[O:33])[NH:27][C:31]2=[O:32])[CH2:36][CH2:35]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCCN1C(=O)CSC1=O
Reactant: O=CC1CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=CC2CC2)S1
Yield: 68.7 %

Procedure:
A solution of 3-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)thiazolidine-2,4-dione (0.20 g, 0.43 mmol), cyclopropanecarbaldehyde (91 mg, 1.3 mmol, 3.0 eq.) and a drop of piperidine in ethanol (15 mL) was refluxed overnight. The volatile phase was removed under reduced pressure. The residue was applied on silica gel and eluted with petroleum:ethyl acetate (3:2) to give 3-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-5-(cyclopropylmethylene thiazolidine-2,4-dione (50 mg) as a white solid. MS (ESI, pos. ion) m/z: 513 (M+1)
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].C([O-])(=O)C.[Na+].Cl.[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:21]>C(O)(=O)C>[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:21][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH:3][CH:1]=[O:2]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC=O
Reaction time: 5 h

Procedure:
In 28.6 g of acetic acid, 14.3 g (0.1 mole) of N-formyl-L aspartic anhydride was suspended and 9.2 g (0.11 mole) of sodium acetate was added with stirring at 5°-10° C. Successively 21.6 g (0.1 mole) of L-phenylalanine methylester hydrochloride was added and the reaction was carried out for 5 hours with stirring at the same temperature. The reaction mixture was then concentrated and 57.2 g of water was added. Precipitated crystals were filtered, washed and dried. Crystals of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester thus obtained were 30.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>ClCCl>[C:16]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:19])[CH2:17][CH3:18]
Reactant: Oc1ccccc1Cl
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Oc1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
A solution, cooled to 10° C., of 2-chlorophenol (100 g, 0.778 mol) in 250 ml of dichloromethane is slowly admixed with triethylamine (120.7 ml). A solution of 60.7 ml of propionyl chloride in 60 ml of dichloromethane is added slowly dropwise to this mixture over the course of an hour. Following the addition of the propionyl chloride, the mixture is allowed to come slowly to room temperature and is stirred at room temperature for a total of five hours. Following removal of the triethylammonium chloride by filtration, the filtrate is diluted with 100 ml of dichloromethane and washed with 0.1 N hydrochloric acid (500 ml), 0.1 M aqueous sodium hydroxide solution (500 ml) and water (500 ml). The organic phase is dried over sodium sulphate (100 g) for three hours. After the drying agent has been removed by filtration, the solvent is removed on a rotary evaporator. Distillation of the oily yellow residue under reduced pressure gives 129.2 g (90% yield) of 2-chlorophenyl propionate as a colourless liquid (bp 90-93° C./0.3 mm).
Reaction SMILES: CC1(C)C2C=CC(C#CC3C=CC(C(O)=O)=CC=3)=CC=2C(SCC)=CC1.CC1(C)C2C=CC(C#CC3C=CC(C(OCC)=O)=CC=3)=CC=2C(S(CC)(=O)=O)=CC1.[CH3:57][C:58]1([CH3:88])[C:67]2[CH:66]=[CH:65][C:64]([C:68]#[C:69][C:70]3[CH:80]=[CH:79][C:73]([C:74]([O:76]CC)=[O:75])=[CH:72][CH:71]=3)=[CH:63][C:62]=2[C:61]([S:81][C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)=[CH:60][CH2:59]1>>[CH3:57][C:58]1([CH3:88])[C:67]2[CH:66]=[CH:65][C:64]([C:68]#[C:69][C:70]3[CH:80]=[CH:79][C:73]([C:74]([OH:76])=[O:75])=[CH:72][CH:71]=3)=[CH:63][C:62]=2[C:61]([S:81][C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)=[CH:60][CH2:59]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(Sc2ccccc2)=CCC3(C)C)cc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(S(=O)(=O)CC)=CCC3(C)C)cc1
Agent: CCSC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC1(C)CC=C(Sc2ccccc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoic acid (Compound 153), 100 mg (0.38 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-phenylthionaphth-3-yl)ethynyl]benzoate (Compound 155) was converted into the title compound (white solid, recrystallized from acetonitrile) using 2 ml of KOH (2N aqueous solution).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[C:14]2[S:15][CH:16]=[C:17]([CH2:19][C:20]([OH:22])=O)[N:18]=2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:44]1[CH2:49][CH2:48][CH:47]([CH2:50][NH2:51])[CH2:46][CH2:45]1>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[C:14]2[S:15][CH:16]=[C:17]([CH2:19][C:20]([NH:51][CH2:50][CH:47]3[CH2:48][CH2:49][O:44][CH2:45][CH2:46]3)=[O:22])[N:18]=2)=[CH:4][CH:3]=1
Reactant: NCC1CCOCC1
Reactant: Cn1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc(F)cc1
Yield: 65.3 %

Procedure:
A solution of the compound (225 mg, 0.709 mmol) obtained in step 5, WSC (204 mg, 1.06 mmol), HOBt (163 mg, 1.06 mmol), TEA (0.198 mL, 1.42 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (98.0 mg, 0.851 mmol) in DMF (2.8 mL) was stirred at 100° C. for 1 hr. The reaction solution was cooled, added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 1→10% methanol/ethyl acetate) to give the title compound (192 mg, 65%) as a yellow powder.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CN(C)C=O.C(O)(=O)C>[CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:25]3[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(CN3CCC(O)CC3)cc2)cc1
Yield: 58.8 %

Procedure:
To a solution of 4-(4-methylsulfonylaminophenoxy)benzaldehyde (2.50 g) in dimethyl formamide (25 mL) were added 4-hydroxypiperidine (1.74 g) and acetic acid (2.5 mL), and the solution was stirred. To the reaction solution was added sodium triacetoxyborohydride (2.18 g) and the solution was stirred for 2 days. After finishing the reaction, the reaction solution was neutralized with 2N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (methylene chloride:methanol=10:1) to give the title compound (1.90 g) having the following physical data.