Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][CH2:37][O:38][C:31]=2[CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>[NH4+].[Cl-].[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:6][C:5]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][CH2:37][O:38][C:31]=3[CH:30]=2)=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Reactant: Brc1ccc2c(c1)OCCO2
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3c(c2)OCCO3)cnc1Cl)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a 50 mL round-bottomed flask was added N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (62 mg, 150 μmol), 1-bromo-3,4-(ethylenedioxy)benzene (32 mg, 150 μmol, Aldrich, St. Louis, Mo.), dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium (II) (12 mg, 15 μmol), Cesium carbonate (98 mg, 300 μmol), dioxane (1 mL), water (0.2 mL). The reaction mixture was stirred at 100° C. for 1 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with saturated NH4Cl (5 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give N-(2-chloro-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (51 mg, 81% yield). MS (EI, pos.) calcd for C19H14ClFN2O4S: 420.0; found 420.9. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.32 (s, 4 H) 6.88-7.09 (m, 4 H) 7.09-7.21 (m, 2 H) 7.74-7.87 (m, 2 H) 8.12 (d, J=2.19 Hz, 1 H) 8.30 (d, J=2.34 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>C(O)C>[N:24]([C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1)=[N+:25]=[N-:26]
Reactant: FC(F)(F)c1nc(Cl)c(-c2ccccc2)c(-c2ccccc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=Nc1nc(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
4-Chloro-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.5 g, 1.5 mmol) (synthesized according to the procedure described in example 1) was refluxed in ethanol (10 ml) containing sodium azide (0.1 g, 1.5 mmol) for 8 hours and allowed to cool to room temperature. The reaction mixture was poured onto ice-water mixture. The solid thus separated was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (0.45 g, 88.3%, HPLC purity 98.5%), mp: 126-128° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=O)[N:9](CC3C=CC(OC)=CC=3OC)[CH:10]([CH3:11])[C:6]=2[C:5]([F:24])=[C:4]([Cl:25])[N:3]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:7]2[CH:8]=[N:9][CH:10]([CH3:11])[C:6]=2[C:5]([F:24])=[C:4]([Cl:25])[N:3]=1
Reactant: COc1ccc(CN2C(=O)c3c(Cl)nc(Cl)c(F)c3C2C)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1N=Cc2c(Cl)nc(Cl)c(F)c21
Yield: 91.6 %

Procedure:
4,6-Dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1-methyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (14.0 g, 36.4 mmol) was dissolved in TFA (70 mL) and triethylsilane (5.1 g, 43.7 mmol). The mixture was heated to reflux and additional triethylsilane (1.3 g, 10.9 mmol) was added until the red-colored solution became clear. TFA and triethylsilane were removed under reduced pressure. The mixture was basified with aq. NaHCO3 to pH 7 and filtered to give the title compound (7.3 g, 85%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 1.42 (d, J=6.8 Hz, 3H), 4.92 (q, J=6.8 Hz, 2H), 9.25 (s, 1H). [M+H] calc'd for C8H5C12FN2O, 235. found, 235.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=O)[CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:20]=2[N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:52]1[CH2:57][CH2:56][N:55](CCN)[CH2:54][CH2:53]1>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:55]3[CH2:56][CH2:57][O:52][CH2:53][CH2:54]3)=[O:17])[CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:20]=2[N:19]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4[nH]3)c2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C([C@@H]1CCCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4[nH]3)c2)C1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
Method L—Step a To a mixture of (R)-1-[4-Chloro-3-(5-fluoro-1H-benzoimidazol-2-yl)-phenyl]-piperidine-3-carboxylic acid hydrochloride (obtained as described in general method 3,4, step e) (0.01 g, 0.27 mmol) in dcm (2 mL), HATU (0.10 g, 0.28 mmol), TEA (0.08 mL, 0.56 mmol) and 2-morpholinoethylamine (0.04 g, 0.33 mmol) were added. The reaction mixture was stirred at room temperature overnight, washed with ammonium chloride solution (2 mL), filtered through a phase separator and organic solvent was removed. The crude was then purified by SCX column and flash chromatography (eluent: gradient from cyclohexane:EtOAc/1:1 to 0:1 to EtOAc:NH3 in MeOH (2M)/10:1). A further purification by preparative HPLC was done to obtain 0.03 g of the title compound (29%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH:20][C:21]([C:23]1[CH:37]=[CH:36][C:26]([CH2:27][NH:28]C(=O)OC(C)(C)C)=[C:25]([CH3:38])[CH:24]=1)=[O:22])[CH3:2].Cl>C(O)C.C(OCC)(=O)C.O.C([O-])(O)=O.[Na+]>[NH2:28][CH2:27][C:26]1[CH:36]=[CH:37][C:23]([C:21]([NH:20][C:4]2[C:5]([CH3:19])=[CH:6][C:7]([C:9]([F:18])([C:14]([F:15])([F:16])[F:17])[C:10]([F:11])([F:12])[F:13])=[CH:8][C:3]=2[CH2:1][CH3:2])=[O:22])=[CH:24][C:25]=1[CH3:38]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CN)c(C)c1
Temperature: 60 °C

Procedure:
Tert-Butyl (4-{[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-carbamoyl}-2-methylbenzyl)carbamate (1.7 g) was dissolved in ethanol (30 ml). To the solution, conc. hydrochloric acid (3 ml) was added and the mixture was stirred under heating at 60° C. for 4 hours. After adjusting to room temperature, the reaction solution was diluted with ethyl acetate and water and neutralized with sodium hydrocarbonate under vigorous stirring. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain 4-(aminomethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-3-methyl benzamide as a crude product (0.81 g). Without further purification, the crude product was used for the next reaction.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:15]([C:16](O)=[O:17])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:15]([C:16]([Cl:3])=[O:17])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)O)c1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)Cl)c1Cl
Yield: 94.9 %

Procedure:
Two drops of dimethylformamide and 11.9 g (0.1 mol) of thionyl chloride were added to a solution of 6.0 g (0.021 mol) of methyl 2-chloro-3-hydroxycarbonyl-4-methylsulfonylbenzoate and 50 ml of dry toluene. The solution was refluxed for 4 hours. After the solvent had been removed in vacuo, 6.2 g of methyl 2-chloro-3-chlorocarbonyl-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2/[C:14](=[CH:22]/[C:23]2[NH:24][CH:25]=[CH:26][C:27]=2[O:28][CH3:29])/[C:15](=[O:21])[NH:16]3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: Nc1cccc(B(O)O)c1
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: COCCOC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc(N)c3)c21
Yield: 64.2 %

Procedure:
Using Method S above, 3-aminophenyl boronic acid (0.16 g, 1.0 mmol) (Lancaster) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.3 g, 0.94 mmol) (Starting Material 7) using (Ph3P)4Pd (0.11 g) as catalyst in aqueous 2M Na2CO3 (0.94 mL, 1.88 mmol) and DME (20 mL) at reflux for 1 day to produce (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield: 0.2 g, 65%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6]/[C:7](/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[N:8]/[OH:9].[Br:16][CH2:17][CH2:18]Br.[OH-].[Na+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[Br:16][CH2:17][CH2:18][O:9][N:8]=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: BrCCBr
Reactant: COCCCC/C(=N/O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: COCCCCC(=NOCCBr)c1ccccc1
Yield: 93.4 %

Procedure:
A mixture of the above oxime (6.5 g, 31 mmol), 1,2-dibromoethane (27 ml, 31 mmol), N,N,N,N-tetrabutylammonium bromide (0.96 g, 3 mmol) and 12N sodium hydroxide (30 ml) was cooled on an icebath with vigorous stirring until the initial exotherm had subsided. The mixture was then stirred at ambient temperature for 16 h. Water (50 ml), 4 N hydrochloric acid (50 ml) and dichloromethane (100 ml) were added and the phases were separated. To the organic phase was added water (50 ml) and pH in the aqueous phase adjusted to 5 with 10% aqueous citric acid. The organic phase was washed with water (50 ml), brine (25 ml) and dried (Na2SO4). The solvent was evaporated in vacuo to give 9.1 g of 5-methoxy-1-phenyl-1-pentanone O-(2-bromoethyl)oxime.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][C:20]3([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:19]2)=[CH:12][CH:11]=1)[C:6]([NH:8][CH3:9])=O.[N-:30]=[N+:31]=[N-:32].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH:5]([C:6]1[N:8]([CH3:9])[N:32]=[N:31][N:30]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][C:20]3([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:19]2)=[CH:12][CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)C(CC(=O)OC)c1ccc(OCC2CCCC3(CCCCC3)C2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)CC(c1ccc(OCC2CCCC3(CCCCC3)C2)cc1)c1nnnn1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.7 %

Procedure:
To a solution of N-methyl-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-succinamic acid methyl ester (178 mg) obtained in Step 7 in acetonitrile (5 mL) were added successively sodium azide (85 mg) and trifluoromethanesulfonic anhydride (0.29 mL), followed by stirring the reaction mixture at room temperature for 24 hours. Then, after addition of saturated aqueous sodium bicarbonate solution, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by thin-layer column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:1) to give 3-(1-methyl-1H-tetrazol-5-yl)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-propionic acid methyl ester (41 mg).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][CH:15]=2)[CH2:10]1)=O)(C)(C)C>C(OCC)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][CH2:18][NH:9][CH2:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Product: COc1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 5° C., 50 mL of a saturated solution of hydrogen chloride in diethyl ether were added dropwise to a mixture of 2.3 g of 7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester in 50 mL of diethyl ether and the reaction mixture stirred for 2 hours at room temperature. The precipitated product (hydrochloride) was separated by filtration, washed with diethyl ether and dried in vacuo. Yield: 1.5 g (7.5 mmol); m.p. 215-218° C.; EI-MS: 163 (M+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCCC1CCOCC1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCOCC1

Procedure:
Prepared similarly to Intermediate 215 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(2-bromoethyl)tetrahydro-2H-pyran.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:14])=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.[CH3:31][O:32]C1C=CC(C=O)=CN=1>>[CH3:31][O:32][C:11]1[N:10]=[CH:9][C:8]([CH2:7][N:5]2[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]3[NH:16][C:17](=[O:30])[C:18]4[CH:23]=[N:22][N:21]([CH:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[C:19]=4[N:20]=3)[CH2:4]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C=O)cn1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Product: COc1ccc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 6-methoxynicotinaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.03 (d, J=2.1 Hz, 1H), 8.01 (s, 1H), 7.69 (dd, J=8.7, 2.5 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 4.83-4.75 (m, 1H), 4.14-4.08 (m, 2H), 3.89 (s, 3H), 3.72-3.68 (m, 1H), 3.62-3.3.54 (m, 3H), 3.33 (t, J=8.3 Hz, 1H), 2.99 (d, J=9.9 Hz, 1H), 2.84-2.82 (m, 1H), 2.57-2.53 (m, 1H), 2.43-2.27 (m, 3H), 1.95-1.82 (m, 3H), 1.19 (d, J=6.6 Hz, 3H). MS: (M+H m/z 425.3).
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2C#N)CC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Ammonium chloride (7.0 g) and iron powder (36.6 g) were added to a mixed solvent of water (180 ml) and ethanol (540 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-(4-tert-butoxycarbonylpiperazin-1-yl)benzonitrile (62.1 g) was added in parts over 40 min and the mixture was stirred at a refluxing temperature for 1 h. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution, and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (50.7 g), melting point: 145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22]2)[N:3]=1.FC(F)(F)C(O)=O.[O:35]1[CH2:38][C:37](=O)[CH2:36]1.[Na]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:37]3[CH2:38][O:35][CH2:36]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22]2)[N:3]=1
Reactant: O=C1COC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)nc(N3CCC(F)(F)C3)c2)CC1
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1(F)CCN(c2cc(C3CCN(C4COC4)CC3)cc(Cl)n2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To an ice-cooled solution of tert-butyl 4-(2-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyridin-4-yl)piperidine-1-carboxylate (0.220 g, 0.547 mmol, 1 equiv) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). After 2 h, the reaction mixture was concentrated in vacuo (25 mm Hg). The resulting residue was dissolved in dichloromethane (10 mL), and the solution was washed with saturated aqueous sodium bicarbonate solution (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in tetrahydrofuran (2 mL). Oxetan-3-one (0.112 mL, 1.10 mmol, 2.00 equiv) and sodium triaetoxyborohydride (366 mg, 1.64 mmol, 3.00 equiv) were sequentially added to the solution at 24° C. After 35 min, the reaction mixture was partitioned between ethyl acetate (10 mL) and saturated aqueous ammonium chloride solution (10 mL). The organic was separated and the aqueous layer was further extracted with ethyl acetate (2×5 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (98:2 dichloromethane/methanol+0.1% ammonium hydroxide) furnished product as a clear oil (166 mg, 85% yield). 1H NMR (CDCl3, 400 MHz), δ: 6.54 (s, 1H), 6.07 (s, 1H), 4.67 (t, J=6.3 Hz, 2H), 4.63 (t, J=6.3 Hz, 2H), 3.82 (t, J=13.2 Hz, 2H), 3.66 (t, J=7.2 Hz, 2H), 3.50 (m, 1H), 2.86 (m, 2H), 2.38-2.52 (m, 3H), 1.72-1.94 (m, 6H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[O:38][C:39]2[C:45]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:44][CH:43]=[CH:42][C:40]=2[CH:41]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[O:38][C:39]3[C:45]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:44][CH:43]=[CH:42][C:40]=3[CH:41]=2)=[CH:9][CH:10]=1
Reactant: COCCCOc1cccc2cc(CCl)oc12
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCOc1cccc2cc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)oc12

Procedure:
Analogously to Method D, 0.339 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy) propoxy]phenyl}piperidine-1-carboxylate and 0.215 g of 2-chloromethyl-7-(3-methoxypropoxy)benzofuran are reacted. The title compound is obtained as a yellow oil. Rf=0.37 (1:2 EtOAc-heptane); Rt=6.26.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CS(C)=O>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
Ethyl 4-fluorobenzoate (20.1 g) was dissolved in dimethyl sulfoxide (50 ml). Piperazine (31.1 g) was added to the solution, and the mixture was stirred at 120° C. for 2 hr. The reaction solution was poured into 1.2 liters of ice water. The precipitated crystal was washed with a mixed solution composed of hexane (500 ml) and diethyl ether (50 ml), was collected by filtration, and was dried under the reduced pressure to give 24.3 g (86.8%) of ethyl 4-(piperazin-1-yl)benzoate.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C([O-])([O-])=O.[K+].[K+].CN[C@H]1[C@H](NC)CCCC1.[Na+].[Cl-]>CN1C(=O)CCC1.[Cu]I.CCOC(C)=O>[CH3:10][O:9][C:4]1[CH:3]=[C:2]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: c1cn[nH]c1
Reactant: COc1cc(Br)ccc1N
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cc(-n2cccn2)ccc1N
Temperature: 150 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of 4-bromo-2-(methyloxy)aniline (400 mg, 1.979 mmol) in anh. NMP (4 mL), at r.t., under N2, were added pyrazole (269 mg, 2 eq), K2CO3 (819 mg, 3 eq), CuI (377 mg, 1 eq) and (1R,2R)-diaminomethylcyclohexane (281 mg, 1 eq). The reaction mixture was stirred at 150° C. for 3 hr. It was cooled down to r.t. and poured into EtOAc/sat.aq. NaCl. The phases were separated and the organic layer was washed with sat.aq. NH4Cl (20 mL) and sat.aq. NaCl (20 mL). The combined aqueous layers were extracted back with EtOAc (20 mL) and the combined organic extracts were dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 7:3) to give the title compound as a brown oil (336 mg, 90%)
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:16](OC)=[O:17])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][OH:17])[CH:3]=1
Reactant: COC(=O)c1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1cc(CO)cc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 108.9 %

Procedure:
A solution (80 mL) of methyl 5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (7.1 g) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/l solution (42 mL) of diisobutylaluminum hydride in toluene was added dropwise over 30 min, and the mixture was further stirred at −78° C. for 1 hr. 1 mol/l Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate, water, saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a brown oil (yield 7.1 g, quantitative).