Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[CH:2]1([C@@:7]([OH:33])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N+:14]([CH3:26])([CH2:17][CH2:18]CC3C=CC=CC=3)[CH2:13][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[Br-].OC1CC[N+](C)(CCCC2C=CC=CC=2)CC1.[Br-].OC1CC[N+](C)(CC[O:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)CC1>>[Br-:1].[CH:2]1([C@@:7]([OH:33])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N+:14]([CH3:26])([CH2:17][CH2:18][O:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH2:15][CH2:16]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C[N+]1(CCOc2ccccc2)CCC(O)CC1
Reactant: C[N+]1(CCCc2ccccc2)CCC(OC(=O)[C@](O)(c2ccccc2)C2CCCC2)CC1
Agent: C[N+]1(CCCc2ccccc2)CCC(O)CC1
Agent: [Br-]
Product: C[N+]1(CCOc2ccccc2)CCC(OC(=O)[C@](O)(c2ccccc2)C2CCCC2)CC1

Procedure:
This compound is prepared by an analogous method to 4-((R)-2-Cyclopentyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(3-phenyl-propyl)-piperidinium bromide (Example 9) by replacing 4-Hydroxy-1-methyl-1-(3-phenyl-propyl)-piperidinium bromide (Intermediate K) with 4-hydroxy-1-methyl-1-(2-phenoxy-ethyl)-piperidinium bromide (Intermediate L).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:9]=[C:10]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=2)[C:14]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:13]1.Br[CH2:37][C:38]#[N:39]>CN(C)C=O>[F:7][C:8]1[CH:9]=[C:10]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH:21][CH2:37][C:38]#[N:39])[CH:19]=2)[C:14]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:13]1
Reactant: N#CCBr
Reactant: Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CCNc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 12 %

Procedure:
Cesium carbonate (3.8 g, 11.7 mmol) was added to an ice-cooled solution of 1-(3,5-difluoro-benzyl)-3-(2-nitro-phenylsulfanyl)-1H-indol-6-ylamine (Example 15a; 3.2 g, 7.79 mmol) in dry dimethyl formamide (15 ml). After 15 min. stirring, bromoacetonitrile (7.4 g, 62.3 mmol) was added and the reaction mixture was heated at 80° C. for 2 h. The mixture was quenched with water and the product was extracted into ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (toluene/acetone 95:5) and crystallization from acetonitrile afforded the title compound (0.42 g). 1H-NMR (CDCl3) δ 8.27 (dd, 1H, J=8.4 and 1.6 Hz), 7.37 (d, 1H, J=8.6 Hz), 7.32 (s, 1H), 7.31 (ddd, 1H, J=8.4, 7.4 and 1.6 Hz), 7.19 (ddd, 1H, J=8.4, 7.4 and 1.6 Hz), 6.99 (dd, 1H, J=8.4 and 1.6 Hz), 6.76 (tt, 1H, J=8.6 and 2.0 Hz), 6.67 (m, 2H), 6.64 (dd, 1H, J=8.6 and 2.0 Hz), 6.54 (d, 1H, J=2.0 Hz), 5.32 (s, 2H), 4.13 (d, 2H, J=6.6 Hz), 4.04 (t, 1H, J=6.6 Hz).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([N+:17]([O-])=O)[CH:14]=[CH:15][CH:16]=1.C(O)(=O)C>C(O)C.C(Cl)(Cl)Cl.[Fe]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[NH2:17]
Reactant: O=[N+]([O-])c1cccc(-c2ccc3ccccc3c2)c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Nc1cccc(-c2ccc3ccccc3c2)c1
Yield: 109.5 %

Procedure:
A mixture of 3-(2-naphthyl)-1-nitrobenzene (5.4 g), iron (3.63 g) and acetic acid (13.0 g) in ethanol (50 ml) was stirred under reflux for 3 hours. The reaction mixture was diluted with chloroform, filtered and treated with saturated sodium bicarbonate solution. The chloroform layer was separated, dried, evaporated and chromatographed on silica gel to give 3-(2-naphthyl)aniline (5.2 g).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=[O:9])=[N:4][N:3]=[N:2]1.[CH2:14]=[C:15]([CH3:17])[CH3:16].CS(O)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:15]([N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=[O:9])=[N:4]1)([CH3:17])([CH3:16])[CH3:14]
Reactant: C=C(C)C
Reactant: O=Cc1ccccc1-c1nnn[nH]1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)n1nnc(-c2ccccc2C=O)n1

Procedure:
In an autoclave, 6.4 g (36.7 mmol) of 2-(tetrazol-5-yl)-benzaldehyde (Step 61.1) in 50 ml of toluene are heated at 110° C. for 1.5 hours with ≈3 g of isobutene and 0.432 ml of methanesulfonic acid. When cold the reaction mixture is diluted with 300 ml of ethyl acetate, washed four times with water and once with brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/ethyl acetate=4:1) and crystallization from hexane with a small amount of diethyl ether at −20° C. yield 2-(2-tert-butyl-tetrazol-5-yl)-benzaldehyde; TLC: Rf=0.36 (hexane/ethyl acetate=10:1).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([CH2:6][NH2:7])[CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].O>O1CCCC1>[CH2:1]=[C:2]1[CH2:5][CH:4]([CH2:6][NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3]1
Reactant: C=C1CC(CN)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CC(CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
Compound 4-2 (3 g, 30.9 mmol) was dissolved in 50 mL of tetrahydrofuran, added Na2CO3 (6.3 g, 60 mmol) and benzyl chloroformate (5.25 g, 30.8 mmol). The mixture was stirred for 12 hours at room temperature, added 100 mL of water, extracted three times with 300 mL of ethyl acetate, combined the organic phases, rotary evaporated to remove solvents and purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give Compound 4-3 (4 g, 56% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12](O)=[O:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1.C(Cl)(=O)C([Cl:22])=O.CN(C=O)C>ClCCCl>[CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12]([Cl:22])=[O:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(C(=O)O)s1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cn1nc(C(F)(F)F)cc1-c1ccc(C(=O)Cl)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxylic acid, oxalyl chloride, DMF and DCE was stirred at room temperature for 90 minutes and then treated in the usual way to give 5-(1-methyl-3trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbonyl chloride as a brown solid.
Reaction SMILES: [OH-].[Na+].[S:3]([O-:15])([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])(=[O:5])=[O:4]>>[S:3]([OH:15])([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])(=[O:4])=[O:5]
Reactant: CCCCC(CC)COS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(CC)COS(=O)(=O)O

Procedure:
This mixture is neutralized with aqueous 8% sodium hydroxide solution, with a molar ratio of sodium hydroxide to all of the acidic species of 1.05. After separation of the two phases obtained, verification is made that the organic phase is free of AA and of 2-ethylhexyl sulphate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][C:12]2([CH3:26])[CH2:17][CH2:16][C:15]3[C:18]([CH3:25])=[C:19]([OH:24])[C:20]([CH3:23])=[C:21]([CH3:22])[C:14]=3[O:13]2)[CH:7]=[CH:6][C:5]=1[OH:27]>[Pd].CO>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2([CH3:26])[CH2:17][CH2:16][C:15]3[C:18]([CH3:25])=[C:19]([OH:24])[C:20]([CH3:23])=[C:21]([CH3:22])[C:14]=3[O:13]2)[CH:7]=[CH:6][C:5]=1[OH:27]
Reactant: COC(=O)c1cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1O
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(CCC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1O
Reaction time: 4 h
Yield: 70.7 %

Procedure:
A mixture of 0.7 g of rac-5-[2-(3,4-dihydro-6-hydroxy2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)ethynyl]-2-hydroxybenzoic acid methyl ester, 0.2 g of 5% palladium on carbon and 20 ml of methanol was hydrogenated at atmospheric pressure for 4 hours. The catalyst was separated by filtration and the filtrate was evaporated. The residue was passed over 10 g of silica gel (70-230 mesh) using methylene chloride. The product was crystallized from ether/hexane to give 0.5 g of colorless crystals with m.p. 108°-110°.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:31])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=2)(=[O:18])=[O:17])[C:8]=1[CH3:30]>C1COCC1.O.C(Cl)Cl>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:31])=[O:4])=[C:8]2[CH3:30])(=[O:18])=[O:17])=[CH:20][C:21]=1[O:27][CH2:28][CH3:29])#[N:26]
Reactant: CCOc1cc(S(=O)(=O)n2c(C)c(CC(=O)OC)c3cccnc32)ccc1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(S(=O)(=O)n2c(C)c(CC(=O)O)c3cccnc32)ccc1C#N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1M Lithium hydroxide (57 μl) is added dropwise to a cooled (0° C.) solution of [1-(4-cyano-3-ethoxy-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.024 g, 0.057 mmol) in THF/water (4 ml of a 1:1 mixture). After stirring at 0° C. for 10 minutes, the reaction mixture is stirred at room temperature for 2.5 hours and then diluted with DCM (4 ml). The resulting mixture is passed through a phase separation cartridge and the aqueous portion is acidified to pH 4 with 1M HCl. This portion is extracted with DCM (2×4 ml) and the organic extracts are combined, passed through a phase separation cartridge, and concentrated in vacuo. The resulting solid is dissolved in ethyl acetate (2 ml) and triturated with iso-hexane (7 ml) to yield the titled compound as a white solid. (MH+ 400)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21].[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:12][C:7]1[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:5](=[O:21])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=c1c2cc(Cl)ccc2nc(CCl)n1-c1ccccc1Cl
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2ccc(Cl)cc2c(=O)n1-c1ccccc1Cl
Yield: 38.8 %

Procedure:
Prepared according to Procedure C using Intermediate 2d (100 mg, 0.294 mmol), adenine (44 mg, 0.323 mmol), K2CO3 (45 mg, 0.323 mmol), and DMF (1 mL). The crude product was recrystallized from EtOH to provide 50 mg of a yellow solid (39%), mp 294.5-294.8° C. (decomposes). 1H NMR (DMSO-d6) δ: 8.10 (d, J=2.2 Hz, 1H); 8.05 (s, 1H); 8.03 (s, 1H); 7.86 (dd, J=2.4, 8.8 Hz, 1H); 7.75-7.82 (m, 2H); 7.59-7.67 (m, 2H); 7.53 (d, J=8.7 Hz, 1H); 7.22 (br s, 2H); 5.13 (d, J=17 Hz, 1H); 4.95 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 159.7, 156.2, 152.9, 151.9, 150.1, 145.5, 141.8, 135.7, 133.1, 132.3, 132.2, 131.9, 131.1, 130.9, 130.0, 129.4, 125.9, 122.0, 118.4, 44.9. MS (ES): m/z 438.0 (M+). Anal. calcd. for C20H13Cl2N7O: C, 54.81; H, 2.99; N, 22.37. Found: C, 54.72; H, 2.87; N, 22.18.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15](=[O:20])C(Cl)(Cl)Cl)[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2].[OH2:21].[OH-].[K+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15]([OH:20])=[O:21])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)n2c1COCC2
Reactant: O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)O)n2c1COCC2
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a solution of 6-(2,2,2-trichloro-acetyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester (Comp. No. 4a) (11 g, 32.3 mmol) in tetrahydrofuran (60 ml) was added water (110 ml) and potassium hydroxide (1.72 g, 30.7 mmol). The mixture was stirred for 5 min, then an additional portion of potassium hydroxide (250 mg) was added and the mixture was stirred for 2 h at 25° C. Tetrahydrofuran was evaporated in vacuo. After addition of 50 ml water, the mixture was acidified with 10 M aqueous hydrochloric acid. The precipitate was filtered off, washed with a small portion of water and dried in vacuo at 55° C. to give 6.56 g (85%) of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid 8-ethyl ester as a white solid. LC/MS (method 3): Rt=1.34 min; m/z=240.03 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:3])[NH2:2].C[Si](Cl)(C)C>ClCCCl>[Cl:10][C:7]1[CH:6]=[C:5]2[C:4]([C:1]([OH:3])=[N:2][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)ccc1C(N)=O
Agent: C[Si](C)(C)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1nc(O)c2ccc(Cl)cc2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To a solution of ethyl 2-(2-carbamoyl-5-chlorophenylamino)-2-oxoacetate (545 mg, 2.02 mmol) and TEA (11 mL, 80 mmol) in DCE (20 mL) was added trimethylsilyl chloride (3.8 mL, 30 mmol) and the solution was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between saturated aq NaHCO3 and DCM (100 mL). The separated aqueous phase was extracted with DCM (2×100 mL) and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10-60% EtOAc/hexanes to afford ethyl 7-chloro-4-hydroxyquinazoline-2-carboxylate as a solid (321 mg, 63%). 1H NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=7.06 Hz, 3 H), 4.39 (q, J=7.10 Hz, 2 H), 7.60-7.74 (m, 1 H), 7.85-7.98 (m, 1 H), 8.11-8.23 (m, 1 H), 12.82 (br s, 1 H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[CH2:6][O:7][CH2:8][O:9][CH3:10])CCC.[Li]CCCC.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]2[C:33]([CH:43]=[O:44])=[CH:34][C:35]3[N:39]([CH3:40])[CH:38]=[N:37][C:36]=3[C:41]=2[F:42])=[C:27]([Cl:45])[CH:26]=1>C1COCC1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]2[C:33]([CH:43]([OH:44])[CH2:6][O:7][CH2:8][O:9][CH3:10])=[CH:34][C:35]3[N:39]([CH3:40])[CH:38]=[N:37][C:36]=3[C:41]=2[F:42])=[C:27]([Cl:45])[CH:26]=1
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C=O)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOCC(O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 64 %

Procedure:
To a solution of tributyl-methoxymethoxymethyl-stannane (864 mg, 2.37 mmol, prepared by the procedure reported in J. Org. Chem. 1988, 53, 4131) in THF (8 mL) at −78° C. is added n-BuLi (0.94 mL, 2.35 mmol, 2.5 M solution in hexane). After stirring for 3 minutes, a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carbaldehyde 10h (59 mg, 0.15 mmol) in THF (2 mL) is added at −78° C. After stirring for 40 minutes at −78° C., the reaction is quenched with saturated aqueous NH4Cl at −78° C., warmed to room temperature, and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, concentrated, and purified by flash chromatography (1.5% MeOH in CH2Cl2) to give the desired product (45 mg, 64%): MS APCI (+) m/z 458, 460 (M+, Br pattern) detected.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:19][CH:20]=2)O1.Br[C:36]1[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=1>O.C(O)C.C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:25][CH2:26]3)=[N:19][CH:20]=2)=[CH:37][N:38]=1
Reactant: Nc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N)nc3)cn2)CC1
Temperature: 120 °C
Yield: 64 %

Procedure:
Sodium carbonate (1.59 g) in water (6.0 mL) was added to a mixture of tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate (0.205 g, 0.526 mmol), 5-bromopyrimidin-2-amine (0.0940 g, 0.54 mmol) and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) in ethanol (6.0 mL) and toluene (6.0 mL). The resulting mixture was heated at 120° C. for 1 h. The mixture was diluted with EtOAc and water. The precipitate was collected by filtration to give the desired product (120 mg, 63.9%). LCMS: (M+H)=357.1.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][CH2:10][C:9](=[O:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:1][C:4]1[C:12]2[O:11][CH2:10][C:9](=[O:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1COc2c1cccc2[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc2c1OCC2=O

Procedure:
By the method of Example 1, Step E, 2.51 g (0.014 mole) of 2,3-dihydro-7-nitro-3-benzofuranone is reacted with 3.1 g (0.056 mole) of powdered iron in 45 mL of glacial acetic acid and 8 mL of water, yielding 7-amino-2,3-dihydro-3-benzofuranone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](I)[CH3:17].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:16][CH3:17]
Reactant: Oc1ccc(F)cc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.7 %

Procedure:
To a solution of 2-bromo-4-fluorophenol (25.8 g) in DMF (100 ml) was added K2CO3 (20.5 g) and ethyl iodide (23.2 g). The mixture was stirred for 24 h at room temperature. Water (400 ml) was added and the mixture was extracted with hexane. The organic phase was washed with water, dried, filtered over a plug of silica gel and evaporated to yield 30.1 g of 2-bromo-1-ethoxy-4-fluoro-benzene as a colorless oil. MS: 220 ([M+H]+).
Reaction SMILES: [C:1]1([CH:7]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([NH:19][C@@H:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3O)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:26]2[O:32][C@H:31]([C:33]([NH:35][CH2:36][CH3:37])=[O:34])[C@@H:29]([OH:30])[C@H:27]2[OH:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1N=C2C(NC=N2)=CN=1>>[CH:20]1([NH:19][C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[C@@H:26]3[O:32][C@H:31]([C:33]([NH:35][CH2:36][CH3:37])=[O:34])[C@@H:29]([OH:30])[C@H:27]3[OH:28])=[C:10]([NH:9][CH2:8][CH:7]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:18]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N[C@@H]4CCC[C@H]4O)nc32)[C@H](O)[C@@H]1O
Agent: Clc1ncc2[nH]cnc2n1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NC4CCCC4)nc32)[C@H](O)[C@@H]1O

Procedure:
(1R-trans)-1-deoxy-1-[6-[(2,2-diphenylethyl)amino]-2-[(2-hydroxycyclopentyl)amino]-9H-purin-9-yl]-N-ethyl-β-D-ribofuranuronamide, from the 2-chloropurine (0.35 g) and (R)-(trans)-2aminocyclopentanol1 (1.0 g) at 130° C. for 10 h. The product was purified on silica eluting with ethyl acetate:methanol 19:1 and then on silica eluting with dichloromethane:methanol:0.880 ammonia (100:8:1). The product had m.p. 122° to 130° C. Analysis found C, 62.6, H, 6.2, N, 16.2%; C31H37N7O5.0.4H2O requires C, 62.6, H, 6.4, N, 16.5%.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)[C:10]=1[NH2:11])=[O:5])C.[Br:22][C:23]1[CH:38]=[CH:37][C:26]([C:27](Cl)=[N:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.O>ClC(Cl)C.C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:4](=[O:5])[C:6]3[N:7]=[N:8][N:9]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:19])=[O:20])[CH:13]=4)[C:10]=3[N:11]=2)=[CH:37][CH:38]=1
Reactant: ClC(=Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: CCOC(=O)c1nnn(-c2cccc(S(C)(=O)=O)c2)c1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)c1cccc(-n2nnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1
Temperature: 150 °C

Procedure:
A mixture of 5-amino-1-(3-methanesulfonyl-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (310 mg, 1 mmol), 4-bromo-N-(4-chloro-phenyl)-benzimidoyl chloride (1.2 mmol) and TiCl4 (2 mmol) in anhydrous dichloroethane (5 mL) is heated to 150° C. for 14 h. After cooling down to room temperature, the mixture is diluted with CH2Cl2 (20 mL) and treated with water (30 mL). The solid is collected by filtration and washed with MeOH (5 ml) to provide the crude 5-(4-bromo-phenyl)-6-(4-chloro-phenyl)-3-(3-methanesulfonyl-phenyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one as yellow solid which is used for next step without further purification.
Reaction SMILES: CO[C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:12](=[O:25])[C:13]3[CH:18]=[N:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]=3[N:15]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl.O[NH:38][C:39](=[NH:41])[CH3:40].CCN(CC)CC>O1CCOCC1.O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([N:11]2[C:12](=[O:25])[C:13]3[CH:18]=[N:17][N:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:14]=3[N:15]=[C:10]2[C:7]2[CH:6]=[CH:5][C:4]([C:3]3[O:33][N:41]=[C:39]([CH3:40])[N:38]=3)=[CH:9][CH:8]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Reactant: CC(=N)NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: Cc1noc(-c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzoic acid methyl ester (50 mg, 0.11 mmol) in dioxane is added NaOH (1N, 400 μL, 0.4 mmol) and stirred at room temperature for 14 h. The mixture is then neutralized by adding HCl (1N, 400 μL, 0.4 mmol) and concentrated. The resulted residue is treated with SOCl2 (1 mL) at room temperature for 1 h and excess SOCl2 is removed under vacuum. The residue is dissolved in CH2Cl2 and added N-hydroxy-acetamidine (12 mg, 0.16 mmol) followed by Et3N (17 mg, 0.16 mmol). After stirring at room temperature for 1 h, the mixture is treated with water (2 mL) and extracted with EtOAc (3×2 mL). The organic layers are combined and concentrated, the residue is dissolved in EtOH (4 mL), NaOAc (40 mg) is added and the mixture is heated to 80° C. for 5 h. After cooling down to room temperature, the solvent is removed and the residue is purified by preparative LC/MS to provide the titled compound 5-(4-chloro-phenyl)-6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one. 1H NMR (CDCl3) δ(ppm) 8.35(s, 1H), 8.12(d, 2H), 8.01(d, 2H), 7.48-7.54 (m, 4H), 7.37 (t, 1H), 7.32(d, 2H), 7.10(d, 2H), 2.47(s, 3H); HPLC-MS calculated for C26H17ClN6O2 (M+H+): 481.1. Found: 481.1.