Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[C:16]([CH2:18][C:19](O)=[O:20])#[N:17].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)C(C)C)(C)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:19](=[O:20])[CH2:18][C:16]#[N:17])[CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1Cc1ccc(F)cc1
Reactant: N#CCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: N#CCC(=O)N1CCN(Cc2ccc(F)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-fluorobenzyl)piperazin-2-one (1.99 g, 9.6 mmol), cyanoacetic acid (0.82 g, 9.6 mmol), EDC (2.02 g, 10.5 mmol), and HOBt (0.15 g, 0.96 mmol) in anhydrous DMF (40 mL), N,N-diisopropylethylamine was added until the solution is about pH 6. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between chloroform and water. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound. The residue was subjected to column chromatography on silica gel eluting with a mixture of 9:1:0.1 mixture of chloroform, methanol, and aq ammonium hydroxide. Collection and concentration of appropriate fractions provided the title product. Residual protic solvent was removed by co-evaporation with benzene (3×). ES MS M-OCH3=276
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH:13]1[CH2:18][CH2:17][O:16][C:14]1=[O:15]>C1COCC1>[N:1]1([CH:13]2[CH2:18][CH2:17][O:16][C:14]2=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1OCCC1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OCCC1n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
An ice cooled solution of indole (9 g, 78 mmol) in dry THF (80 mL) was treated with oil free sodium hydride (2.25 g, 94 mmol). After 1 hour, a solution of 2-bromobutyrolactone (14.6 mL, 78 mmol) in dry THF (20 mL) was added dropwise. After stirring overnight at ambient temperature, the mixture was poured on crushed ice, extracted with ethyl acetate (3×), dried, and evaporated. The residue was purified by flash chromatography on silica gel with a hexane/ethyl acetate gradient (9:1 to 7:3). Evaporation of the eluting solvent gave 8 g of a yellowish oil (52% of theory).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15](=[N:22]C(OC(C)(C)C)=O)[N:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1)(C)(C)C>C(Cl)Cl.O>[N:16]1([C:15]([NH2:22])=[NH:14])[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCSCC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)N1CCSCC1
Reaction time: 72 h

Procedure:
Trifluoroacetic acid (50 mL, 0.073 mol) was added dropwise to a stirred mixture of (tert-Butoxycarbonylimino-thiomorpholin-4-yl-methyl)-carbamic acid tert-butyl ester (21 g, 0.0723 mol) in DCM (200 mL) and water (10 mL). After 3 days at rt, the solvent was evaporated and re-evaporated with 2-propanol. The resulting semi-solid was triturated with 10% 2-propanol/Et2O. The solid was filtered off and was washed with 10% 2-propanol/Et2O and then with Et2O. The product was dried in vacuo over phosphoric oxide, to give 15.72 g as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19]([O:21]CC)=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O1CCCC1.O.Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19]([OH:21])=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reaction time: 0.33 h

Procedure:
A suspension of ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate from Step 2 (52.5 g, 140.7 mmol) in a mixture of tetrahydrofuran (400 mL), methanol (400 mL) and 1N aqueous sodium hydroxide (280 mL) was heated at ca 50° C. with stirring for 20 minutes. After cooling, the mixture was diluted with water (300 mL) and 1N aqueous HCl (325 mL) was added. After stirring for 45 minutes, the precipitate was filtered, washed well with water and dried to afford the 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid as a cream-colored solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:19][C:20]3[N:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH3:38])[C:22](=[O:31])[C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:30])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12.[Al].C(Br)(Br)(Br)Br.[CH2:45]([O:47][P:48]([O-:52])[O:49][CH2:50][CH3:51])[CH3:46].C(N(CC)CC)C>C1COCC1>[P:48]([OH:52])([OH:49])([O:17][C:15]1[CH:14]=[C:13]([F:18])[CH:12]=[C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH2:19][C:20]3[N:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH3:38])[C:22](=[O:31])[C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:30])[N:9]=2)[CH:16]=1)=[O:47].[P:48]([O:49][CH2:50][CH3:51])([O:47][CH2:45][CH3:46])([O:17][C:15]1[CH:14]=[C:13]([F:18])[CH:12]=[C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH2:19][C:20]3[N:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH3:38])[C:22](=[O:31])[C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:30])[N:9]=2)[CH:16]=1)=[O:52]
Reactant: Cc1ccccc1-n1c(Cn2nc(-c3cc(O)cc(F)c3)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Reactant: CCOP([O-])OCC
Agent: BrC(Br)(Br)Br
Agent: [Al]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)Oc1cc(F)cc(-c2nn(Cc3cc4cccc(C)c4c(=O)n3-c3ccccc3C)c3ncnc(N)c23)c1
Product: Cc1ccccc1-n1c(Cn2nc(-c3cc(F)cc(OP(=O)(O)O)c3)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 124.5 %

Procedure:
3-((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one 4301 (250 mg, 0.5 mmol) was dissolved in anhydrous THF (15 mL) in a round bottom flask in dark (covered by aluminum foil) and cooled to 0° C. under an argon atmosphere. CBr4 (498 mg, 1.5 mmol) was added followed by diethylphosphite (129 μL, 1.0 mmol) and triethylamine (417 μL, 1.5 mmol). The resulting mixture was stirred in dark from 0° C. to RT for 16 h. The mixture was then partitioned between ethyl acetate and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methanol and dichloromethane to afford the desired product, 3-(4-amino-1-((8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenyl diethyl phosphate 4302 (200 mg, 62% yield) as an off-white solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.C(N(CC1C=CC=CC=1)[C:17](=[O:22])[CH2:18][O:19][CH2:20][CH3:21])C.[BH4-].[Na+]>C1COCC1>[Br:13][C:9]1[N:8]=[C:7]([CH:17]([OH:22])[CH2:18][O:19][CH2:20][CH3:21])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCOCC(=O)N(CC)Cc1ccccc1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC(O)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 37.1 %

Procedure:
To a solution of n-butyllithium (1.6M in hexanes, 4.19 mL, 6.70 mmol) in anhydrous THF (4.0 mL) under nitrogen at −78° C. was added a solution of 2,6-dibromopyridine (1.59 g, 6.71 mmol) in anhydrous THF (9.5 mL) drop-wise over 1 h. The resulting dark green solution was stirred at −78° C. for 15 min and then treated with N-ethyl-2-(ethyloxy)-N-(phenylmethyl)acetamide (1.93 g, 8.70 mmol), washing in with anhydrous THF (1.0 mL). The resulting green solution was stirred at −78° C. for 15 min and was then treated with a solution of AcOH (0.42 mL) in MeOH (7.00 mL) to give a orange solution which was then treated with NaBH4 (0.38 g, 10.04 mmol). This mixture was removed from the cooling bath and allowed to warm to room temperature over 2 h. The mixture was then treated with saturated aqueous. NH4Cl (50 mL) and the products extracted with EtOAc (2×50 mL). The combined organic layer was then washed with brine (100 mL), dried (MgSO4) and the reduced in vacuo to give a yellow oil. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 1:1) afforded the title compound as a white solid (612 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[ClH:34].[N:35]1([C:40](N)=[NH:41])C=CC=N1.C(OCC)C>CN(C)C=O>[ClH:34].[ClH:34].[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][N:21]([C:40]([NH2:41])=[NH:35])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCC(COc3ccc4c(c3)CNCC4)CC2)ccn1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 127.9 %

Procedure:
To a solution of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline (50 mg) in dimethylformamide (0.5 ml) were added diisopropylethylamine (0.027 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (23 mg), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, diethyl ether was added and insoluble material was collected by filtration. The obtained solid was washed with diethyl ether. A part (45 mg) of the obtained solid was treated with hydrogen chloride-methanol and dried under reduced pressure to give the title compound (44 mg).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]#[C:15][Si](C)(C)C)[S:13][C:6]=12.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(O)=O>[C:14]([C:12]1[S:13][C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:2]=2[F:1])[CH:11]=1)#[CH:15]
Reactant: C[Si](C)(C)C#Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of the alkyne 409 (2.2 g, 5.69 mmol) in THF (30 ml) was added a solution of TBAF (8.53 mL, 1.5 eq, 1M soln in THF) in HOAc (30 ml), and the reaction mixture was stirred at RT overnight. It was then concentrated to dryness and partitioned between water and EtOAc. The organic phase was washed well with satd. NaHCO3 soln, collected, dried over anhydrous Na2SO4, filtered and concentrated. The crude mixture was adsorbed onto silica gel then purified by column chromatography (30% EtOAc in hexane) to afford 410 (1.4 g, 72% yield). LCMS: 415.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:12][C:13](=O)[CH3:14])[CH2:7]2.C(N(S(F)(F)[F:22])CC)C.[F-:25].[Cs+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:12][C:13]([F:22])([F:25])[CH3:14])[CH2:7]2
Reactant: CC(=O)CN1CCc2c(Br)cccc2C1
Reactant: CCN(CC)S(F)(F)F
Reactant: [F-]
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(F)(F)CN1CCc2c(Br)cccc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(5-bromo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-one (962 mg, 3.59 mmol), diethylamino sulfur trifluoride (1.74 g, 10.8 ml) in DCM (12 ml) is added cesium fluoride (151 mg, 1 mmol) in small portions, then a few drops of TFA at room temperature. The mixture is stirred for 18 hours at room temperature. To this solution is added saturated aqueous NaHCO3 to quench the reaction. The aqueous layer is extracted with DCM (50 ml×3). The combined organic layers are washed with water, brine, dried over MgSO4 and concentrated. The residue is purified by silica gel flash chromatography, eluted with 20% ethyl acetate in hexanes to yield 5-Bromo-2-(2,2-difluoropropyl)-1,2,3,4-tetrahydroisoquinoline as a brown oil. LC-MS m/z: 291.1 (M+1).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:13]1([CH2:19][NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.CN1CCC[C:30]1=[O:34]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]1([CH2:19][NH:20][C:30]([C:2]2[C:3]3[CH:4]=[CH:5][CH:6]=[N:7][C:8]=3[CH:9]=[CH:10][C:11]=2[CH3:12])=[O:34])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1ccc2ncccc2c1Br
Reactant: CN1CCCC1=O
Reactant: NCC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2ncccc2c1C(=O)NCC1CCCCC1

Procedure:
Prepared according to the method of example 42, using 5-bromo-6-methylquinoline (prepared according to the method of Khimiya Geterotsiklicheskikh Soedinenii 1988, 8, 1084) (4.0 g), cyclohexanemethylamine (4.2 mL), triethylamine (2.4 mL), dichlorobis(triphenylphosphine)palladium(II) (1.6 g) in N-methylpyrrolidinone (40 mL) to afford the title compound (3.9 g)
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+].CI.CN(C)C=O>O>[CH3:29][O:19][C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:28])[C:10]2[C:15]([C:16]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=2)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A mixture of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg), potassium carbonate (95 mg), methyl iodide (43 μl) and N,N-dimethylformamide (DMF) (5 ml) was stirred at room temperature for 3 hrs. After diluting with water, the mixture was extracted with ether and the extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and ethyl acetate and n-hexane was added to the residue and the mixture was crystallized to give the title compound (96 mg, 62%).
Reaction SMILES: [OH-:1].[Na+].[O:3]=[C:4]1[NH:9][C:8]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16][C:7]=2[N:6]2[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=[C:5]12>O1CCOCC1>[O:3]=[C:4]1[NH:9][C:8]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16](=[O:1])[C:7]=2[N:6]2[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=[C:5]12
Reactant: [OH-]
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1ccccc1C3
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1cn2c3c([nH]c(=O)c2n1)-c1ccccc1C3=O

Procedure:
5 ml of 1N sodium hydroxide are added to a suspension of 0.2 g of ethyl 4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate in 15 ml of dioxane, and the reaction mixture is stirred vigorously while compressed air is bubbled for 15 hours. After addition of 10 ml of distilled water the mixture is acidified with concentrated hydrochloric acid. The precipitate form is filtered off, washed with water and dried to produce 0.13 g of 4,5-dihydro-4,10-dioxoimidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylic acid in the form of a brown powder whose melting point is higher than 260° C. (1H spectrum in DMSO, T=300K, δ in ppm (200 MHz): between 7.35 and 7.65 (3H, m, CH arom. ), 7.75 (1H, d, J=7 Hz, CH arom.), 8.38 (1H, s, CH arom.), 12.5 (1H, s, NH)).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([F:26])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([CH:33]=O)[CH:29]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([F:26])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:33][C:30]3[CH:29]=[C:28]([CH3:27])[O:32][N:31]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: Cc1cc(C=O)no1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(CC2=C(O)CC(CCc3ccc(OC(C)C)c(F)c3)(C3CCCC3)OC2=O)no1

Procedure:
The title compound was prepared by coupling 6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione from Step 1 of Example B(14), to 5-Methyl-isoxazole-3-carbaldehyde using the AlCl3/reduction procedure described for Example B(13).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)=[C:10]([CH3:23])[C:9]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(O[N:42]1N=[N:49][C:44]2C=CC=N[C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NCC#N>CN(C=O)C.CCOC(C)=O>[C:43]([CH2:44][NH:49][C:20]([CH:17]1[CH2:16][CH2:15][N:14]([C:11]2[N:12]=[N:13][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:9]([CH3:24])[C:10]=2[CH3:23])[CH2:19][CH2:18]1)=[O:22])#[N:42]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCC(C(=O)O)CC2)c1C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(C(=O)NCC#N)CC2)c1C
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To a solution of 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid (350 mg, 1.08 mmol) in DMF (10 mL) is added DIPEA (0.94 mL, 5.4 mmol) and HATU (490 mg, 1.29 mmol). After being stirred at 25° C., aminoacetonitrile hydrochloride (119 mg, 1.29 mmol) is added. The mixture is stirred for 2 h, and diluted with EtOAc (20 mL) and washed with H2O (3×10 mL). The organic layer is dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography (CH2Cl2/MeOH: 97%/3%) to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid cyanomethyl-amide (280 mg, 72%).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]#N)=[CH:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[OH2:18].[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][C:11]([C:8]1[CH2:9][CH2:10][C:5]2([CH2:4][CH2:3][CH2:2][CH2:1]2)[CH2:6][CH:7]=1)=[O:18])[CH3:20]
Reactant: N#CC1=CCC2(CCCC2)CC1
Reactant: CCO
Reactant: O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of spiro[4.5]dec-7-ene-8-carbonitrile (2.8 g) obtained in Step 2 in ethanol (30 mL) was added concentrated sulfuric acid (3 mL), followed by heating the reaction mixture under reflux while stirring for 5 days. After cooling down to room temperature and adding water, the reaction mixture was extracted with ethyl acetate twice. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:4) to give spiro[4.5]dec-7-ene-8-carboxylic acid ethyl ester (2.8 g).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:31][C:32]1[C:33]([F:42])=[C:34]2[C:40]([NH2:41])=[CH:39][NH:38][C:35]2=[N:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:31][C:32]1[C:33]([F:42])=[C:34]2[C:40]([NH:41][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:39][NH:38][C:35]2=[N:36][CH:37]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CS(=O)(=O)CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
2-(Methylsulfonyl)acetic acid (601 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 (50 mL) was added. The resulting suspension was filtered, and the solid was rinsed with DCM and water. After drying, N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)acetamide (503 mg, 66.1% yield) was obtained as a solid.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[C:33]([F:36])([F:35])[F:34])[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].[F:37][C:38]1[CH:47]=[CH:46][C:41]([C:42](=O)[CH2:43]Br)=[CH:40][CH:39]=1>>[F:35][C:33]([F:34])([F:36])[C:24]1[CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=[CH:28][C:23]=1[CH2:22][N:4]([C:2]1[S:3][CH:43]=[C:42]([C:41]2[CH:46]=[CH:47][C:38]([F:37])=[CH:39][CH:40]=2)[N:1]=1)[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])=[CH:20][CH:21]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(N)=S)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2nc(-c3ccc(F)cc3)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 4-fluorophenacyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([F:17])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1.[CH2:25](I)[CH:26]([CH3:28])[CH3:27].[H-].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([F:17])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:11]=1
Reactant: CC(C)CI
Reactant: CCOC(=O)CCc1cc(F)c(OCc2cccc(O)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(F)c(OCc2cccc(OCC(C)C)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
Ethyl 3-{3,5-difluoro-4-[(3-hydroxybenzyl)oxy]phenyl}propanoate (200 mg, 0.59 mmol) was dissolved in DMF (10 mL), isobutyl iodide (339 μL, 3.0 mmol) and sodium hydride (47 mg, 1.2 mmol) were added thereto, and then the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 80:20) to give the title compound (186 mg, yield 80%) as an oily matter.