Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[NH2:3][C@@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][N:8]=1>C(Cl)(Cl)Cl>[NH2:3][C@@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]([Br:1])=[CH:9][N:8]=1
Reactant: BrBr
Reactant: N[C@H](CNc1nccc(-c2ccncc2)n1)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N[C@H](CNc1ncc(Br)c(-c2ccncc2)n1)Cc1ccccc1
Reaction time: 48 h

Procedure:
Bromine (787 •l, 15.28 mmol) was added to a stirring solution of 2-(((S)-2-amino-3-phenylpropyl)-amino)-4-(4-pyridyl)-pyrimidine (2.33 g, 7.64 mmol) in chloroform (25 ml). Stirring was continued for 2 d. The mixture was partitioned between dichloromethane and aqueous sodium hydrogencarbonate. The organic solution was washed with brine, dried and evaporated. The resultant product was purified on a column of silica gel (dichloromethane-methanol-conc. ammonium hydroxide=92:8:0.6). MS (m/z): 384.0, 386.0 (M+H)+; C18H18BrN5 requir. 384.3.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2[C@H:32]3[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)[C:26](=[O:33])N(CCO)N=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2[C@H:32]3[C@H:27]([CH2:28][CH:29]=[CH:30][CH2:31]3)[C:26](=[O:33])[N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)[N:12]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: CC(C)(C)c1ccc(NN)cc1
Product: COc1ccc(C2=NN(c3ccc(C(C)(C)C)cc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from 4-tert-butylphenylhydrazine and compound C as described for compound 35. After evaporation of the solvent, the compound was crystallized from ethanol. M.p. 197°-199° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[CH2:31][C:32]([OH:34])=[O:33])=[CH:5][CH:4]=1)#[N:2].C(C1C=CC([C@@H]2C3C(=O)CCCC=3N(C3C=CC=C(C(F)(F)F)C=3)C(=O)N2CC(OC)=O)=CC=1)#N>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[CH2:31][C:32]([OH:34])=[O:33])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Agent: COC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)[C@H]1c1ccc(C#N)cc1
Product: N#Cc1ccc([C@@H]2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1

Procedure:
The title compound is prepared in analogy to 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(tri-fluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)acetic acid (example 32), using (R)-methyl 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)acetate (example 31A, 30 mg, 62 μmol) as starting material. Yield: 27 mg; ESI mass spectrum [M+H]+=470; Retention time: 1.09 min (V001—006).
Reaction SMILES: [I-].[O:2]1CCOC1C1C=[NH+]C=CC=1.[OH-].[K+].C1(C)C=CC=CC=1.[CH3:22][N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[O:33][CH2:32][CH2:31][O:30]2)[C:24]1=O>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:22][N:23]1[CH:24]=[C:25]([CH:29]2[O:33][CH2:32][CH2:31][O:30]2)[CH:26]=[CH:27][C:28]1=[O:2]
Reactant: c1c[nH+]cc(C2OCCO2)c1
Reactant: Cn1cccc(C2OCCO2)c1=O
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1cc(C2OCCO2)ccc1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
3-(1,3-Dioxolan-2-yl)-1-pyridinium iodide (1.85 g, 6.31 mmol) was dissolved in water (40 mL). To this, a solution of potassium ferricyanide (22.9 g, 69.4 mmol) in water (50 mL) was added dropwise under a nitrogen atmosphere at 0° C. over 1 hour. To this, a solution of potassium hydroxide (55.9 g, 100 mmol) in water (9.5 mL) was added dropwise at the same temperature over 30 minutes. To this, toluene (65 mL) was added and the mixture was stirred at 40° C. for 30 minutes. Then, extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by column chromatography (hexane/ethyl acetate=1/1) to give a 73:27 mixture (933 mg, yield: 82%) of 1-methyl-5-(1,3-dioxolan-2-yl)-2(1H)-pyridone and 1-methyl-3-(1,3-dioxolan-2-yl)-2(1H)-pyridone.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.C(O)C.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>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH3:11])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Cn1ccc2ccc(Br)cc21
Reactant: CC(C)(C)c1ccc(B(O)O)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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1ccc2ccc(-c3ccc(C(C)(C)C)cc3)cc21
Yield: 56.3 %

Procedure:
Following the procedure described in Step 2 of Example 5, 6-bromo-1-methyl-1H-indole (1.12 g , 5.33 mmol) was coupled to 4-(tert-butyl)phenylboronic acid (1.07 g, 6.00 mmol), using tetrakis(triphenylphosphine)palladium (0.655 g, 0.567 mmol), and potassium carbonate (2.94 g, 21.3 mmol) in water (10.6 mL), ethanol (2.2 mL), and toluene (23 mL). Purification by flash chromatography (Biotage apparatus) using 0-1% ethyl acetate in hexane as an eluant then drying at 60° C. yielded 6-[4-(tert-butyl)phenyl]-1-methyl-1H-indole as a yellow solid (0.790 g, 56%), mp: 92-94° C. 1HNMR (200 MHz, DMSO-d6): δ 7.55-7.7 (m, 5H), 7.45 (d, 2H, J=7.5 Hz), 7.3 (d, 2H, J=8.5 Hz), 6.6 (d, 1H, J=3.5 Hz), 3.9 (s, 3H), and 1.3 ppm (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].CC1(C)COC2=CC3OC[C:32]4([C:42]=3[CH:43]=C12)[C:40]1[C:35](=CC=C[CH:39]=1)NC4=O.BrCCCC1CC1.BrCC1OC(C(F)(F)F)=CC=1>>[CH:40]1([CH2:32][CH2:42][CH2:43][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[CH2:39][CH2:35]1
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: BrCCCC1CC1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(CCCC2CC2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (3-bromopropyl)cyclopropane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (51%) as a white solid: mp 111-113° C.; MS (ES+) m/z 364.3 (M+1).
Reaction SMILES: [CH2:1]([S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1)[CH2:2]CCC.C(S)C>>[CH2:1]([S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:16][CH2:15][N:14]([CH2:19][CH2:18]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1)[CH3:2]
Reactant: CCCCCSc1c[nH]nc1C1CN2CCC1CC2
Solvent: CCS
Product: CCSc1c[nH]nc1C1CN2CCC1CC2
Yield: 30 %

Procedure:
Compound 49D was prepared following the procedure as described for the synthesis of compound 49B (see Scheme 10) using ethanethiol as reagent. Subsequent purification by flash chromatography (EtOH to EtOH/triethylamine 99/1) afforded compound 49D.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].I[CH3:18]>O1CCCC1.C(OCC)(=O)C>[CH3:18][O:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CO[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.42 h
Yield: 98.2 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-hydroxypiperidine-1-carboxylate (Preparation 128, 1.6 g, 7.95 mmol) in anhydrous tetrahydrofuran (35 ml) was added sodium hydride (60% dispersion in oil, 0.32 g, 7.95 mmol) in portions. The resulting mixture was stirred for 25 min then iodomethane (2.27 g, 16 mmol) was added dropwise and the reaction mixture was stirred for 17 h. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with brine (5% solution, 150 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography on silica gel (70 g) eluting with dichloromethane:methanol (100:1 and then 50:1) to give a yellow oil (1.68 g). The trace of iodine was removed by dissolving the product in ethyl acetate (50 ml) and washing with aqueous sodium metabisulphite (5% solution, 2×35 ml), water (35 ml) and aqueous sodium hydrogen carbonate (5% solution, 35 ml). The organic extracts were dried (MgSO4) and concentrated in vacuo to give the desired product as a colourless oil (1.62 g).
Reaction SMILES: [Ca+2].[OH:2][CH:3]([CH2:7][CH2:8][S:9][CH3:10])[C:4]([O-:6])=[O:5].O[CH:12](CCSC)C([O-])=O.[Cl-].[Na+]>Cl>[OH:2][CH:3]([CH2:7][CH2:8][S:9][CH3:10])[C:4]([O:6][CH3:12])=[O:5]
Reactant: CSCCC(O)C(=O)[O-]
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Product: COC(=O)C(O)CCSC
Reaction time: 0.5 h
Yield: 128.3 %

Procedure:
A solution of DL, 2-hydroxy-4-methylmercaptobutyric acid calcium salt (2.2 g) in 0.5M HCl (50 mL) was saturated with sodium chloride, extracted exhaustively with EtOAc, which was dried (MgSO4), filtered and concentrated. The residue was dissolved in methanol (10 mL) and trimethylsilyldiazomethane (2M in hexane) was added until the yellow color persisted for 30 min. The reaction was quenched by addition of glacial acetic acid and concentrated. The residue was purified by silica gel chromatography eluting with 30% EtOAc/hexane to give the title compound as a light yellow oil (1.37 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](=[O:25])[N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([CH3:18])[C:16]=2[CH3:17])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].CC(C)([O-])C.[K+].Cl[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH2:41])=[O:40])[CH:34]=1>CN(C=O)C>[CH3:18][N:15]1[C:16]([CH3:17])=[C:12]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:33]3[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH2:41])=[O:40])[CH:34]=3)=[C:2]([F:1])[CH:3]=2)=[O:11])[C:13](=[O:25])[N:14]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(C(=O)Nc2ccc(O)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.6 %

Procedure:
To a solution of N-(3-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (7.18 g, 21.1 mmol) in DMF (200 mL) was added potassium tert-butoxide (7.08 g, 63.2 mmol). The solution was stirred at rt for 20 minutes, followed by the addition of 4-chloropicolinamide (4.27 g, 25.2 mmol). The reaction was heated at 120° C. for 3 hours, then concentrated to 2 mL in vacuo, and diluted with water (60 mL). The precipitate was obtained by filtration, and then washed with water (10 mL). The crude product was purified by a silica gel column chromatography (DCM/EtOAc/MeOH (v/v/v)=1/1/0.05) to give the title compound as a yellow solid (4.15 g, 43% yield).
Reaction SMILES: COC(=O)[C:4]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([OH:20])=[C:6](C(OC)=O)[C:5]=1[OH:21].Cl.C1C=CC=CC=1>O.[OH-].[Na+].CCOCC>[C:14]1([C:13]2[CH:12]=[C:11]([OH:20])[CH:6]=[C:5]([CH:4]=2)[OH:21])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1c(O)cc(-c2ccccc2)c(C(=O)OC)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: Oc1cc(O)cc(-c2ccccc2)c1
Reaction time: 14 h
Yield: 54.8 %

Procedure:
6.00 g (0.0199 mole) of 2,4-dihydroxy-6-phenyl-isophthalic acid dimethyl ester is dissolved under nitrogen in 40 ml of water and 40 ml of 2N sodium hydroxide solution. The light-red solution is refluxed for one hour; it is then cooled with an ice bath and carefully acidified with 8.0 ml of concentrated hydrochloric acid (carbon dioxide evolution). The mixture is then refluxed and boiled for 14 hours in a nitrogen atmosphere. The emulsion obtained after cooling is extracted twice with 100 ml of ether each time. The combined ether layers are dried with magnesium sulphate and concentrated in vacuo to obtain 3.98 g of crude product in the form of yellow crystals. This crude product is dissolved in 20 ml of ether; 50 ml of benzene is added and the ether then distilled off. 5-Phenylresorcinol crystallises out on standing. After cooling, there is added 50 ml of hexane, and the crystals are filtered off under suction; this yields 2.44 g of cream-coloured crystals, M.P. 154°-158°. Repeated crystallisation from 40 ml of benzene with the addition of 40 ml of hexane yields 2.03 g of 5-phenylresorcinol as colourless crystals, M.P. 157° - 158°.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6](=[O:8])[NH:28][C:27]2[CH:29]=[CH:30][C:24]([C:23]([F:22])([F:31])[F:32])=[CH:25][CH:26]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)OC(C(=O)O)c1ccc(Br)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(C(=O)Nc1ccc(C(F)(F)F)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a cooled solution (0 degrees Celcius) of acetoxy-(4-bromo-phenyl)-acetic acid (6.1 g, 22 mmol) in dichloromethane (30 mL) was added oxalyl chloride (4.2 g, 33 mmol) dropwise. After stirring for an additional 1 hour at room temperature, the reaction mixture was concentrated in vacuo and dried under vacuum. The acid chloride intermediate was dissolved in dichloromethane (20 mL) and then added over 1 hr to a solution of 4-trifluoromethylaniline (4.0 g, 25 mmol) and triethylamine (3.6 mL, 25 mmol) in dichloromethane (10 mL) at 0 degrees Celcius. The reaction was then allowed to warm to room temperature and stirred for 30 minutes. The reaction was diluted with dichloromethane and then washed twice with 1N HCl, twice with saturated sodium bicarbonate, and twice with brine. The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo to furnish a yellow solid. The solid was washed with ether to obtain a white solid (5.7 g, 61%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]3[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:40]N(C)C=O.[H-].[Na+].CI>>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([N:23]([CH3:40])[C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:28]3[CH3:33])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cn1c(-c2ccccc2)nc2c(N[C@@H]3C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C3)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(c1ncnc2c1nc(-c1ccccc1)n2C)[C@@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
To a solution of N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]-9-methyl-8-phenyl-9H-purin-6-amine (200 mg, 0.0004 mol) in N,N-dimethylformamide (10 mL, 0.1 mol) was added sodium hydride (0.112 g, 0.00280 mol). The mixture was stirred for 30 minutes and to this was added methyl iodide (0.05 mL, 0.0008 mol) and the mixture was stirred overnight. The reaction was quenched by addition of saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate, washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 10% MeOH/DCM) to obtain 200 mg (100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][C@@H:7]([N:9]=[N+]=[N-])[CH2:6][N:5]1[C:12](=[O:23])[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15]>[Pd].CO>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][C@@H:7]([NH2:9])[CH2:6][N:5]1[C:12](=[O:23])[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH3:15]
Reactant: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)CN(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
10% Palladium on activated carbon (75 mg) was added to a solution of trans-4-azido-1-(N-tert-butoxycarbonyl-N-methylglycyl)-L-proline methyl ester (C, 0.75 g) in methanol (50 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hr. After the catalyst were removed by filtration, the filtrate was evaporated in vacuo to afford the title compound (0.54 g).
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][O:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:22][C:23]#[N:24].[C:25](=O)([O:29]CC)[O:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1.C(O)C>[C:23]([CH:22]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:8]=1[O:7][CH3:6])[C:25]([O:26][CH2:27][CH3:28])=[O:29])#[N:24]
Reactant: COc1c(CC#N)cccc1Oc1ccccc1C
Reactant: CCOC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Yield: 96.5 %

Procedure:
A mixture of sodium ethoxide prepared from ethanol (20 ml) and sodium metal (480 mg), 2-[2-methoxy-3-(o-tolyloxy)phenyl]acetonitrile (5 g) and diethyl carbonate (9.4 g) in toluene (50 ml) was treated in a similar manner to that of Example 10-(4) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (6.2 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29]([OH:31])=O)[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][C:42]2[CH:43]=[C:44]([C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][NH2:55])[CH:49]=3)[CH:45]=[CH:46][CH:47]=2)[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CS(C)=O.C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([C:29]([NH:55][CH2:54][C:50]4[CH:49]=[C:48]([C:44]5[CH:45]=[CH:46][CH:47]=[C:42]([CH2:41][CH:38]6[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]6)[CH:43]=5)[CH:53]=[CH:52][CH:51]=4)=[O:31])[N:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CC4CCN(C)CC4)c3)c2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
Process (B) In an alternate preparation of the titled compound, to a solution of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (45 mg, 0.1 mmol) in DMSO (1 mL) was added 1-{3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methanamine (28 mg, 0.095 mmol), HBTU (42 mg, 0.11 mmol) and Et3N (0.021 mL, 0.15 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 18 h. The reaction was quenched with H2O (2 drops), purified with a Gilson HPLC (with 0.1% TFA), concentrated, re-dissolved in EtOAc, washed with NaOH (1N), dried over Na2SO4, filtered, concentrated and dried with a high vacuum oil pump to afford the title compound as a white solid 38.5 mg (53%). LC-MS m/z 729 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[CH3:22][S:23]([C:26]1[CH:31]=[C:30]([C:2]2[S:6][C:5]([C:7]3[N:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[CH:8]=3)=[CH:4][CH:3]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(Br)s1
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: CN(C)C=O
Product: CCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Temperature: 90 °C
Yield: 67.1 %

Procedure:
A stirred solution of compound 15 (1.5 g, 3.9 mmol) and 3-(methylsulfonyl)phenylboronic acid (1.2 g, 5.8 mmol) in DMF (10 mL) was degassed with argon. Tetrakis(triphenylphosphine)palladium(0) (450 mg, 0.3 mmol) was added and the reaction degassed for 30 min. Sodium carbonate (1.03 g, 9.0 mmol) was added to the reaction mixture, the reaction was degassed with argon for 30 min and heated to 90° C. for 3 h. Solvent was removed and the reaction mixture diluted with water (30 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with saturated brine, dried over sodium sulphate and concentrated. The crude reaction mixture was purified by column chromatography using 30% ethyl acetate in hexane to afford 16 (1.2 g, 67%). LCMS: 459.20 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ 8.13 (s, 1H), 8.05 (d, 1H, J=7.6 Hz), 7.91 (d, 1H, J=7.6 Hz), 7.82 (d, 1H, J=4 Hz), 7.75 (t, 2H, J=7.6 Hz) 7.20 (s, 1H), 5.40 (s, 2H), 4.01-4.23 (m, 2H), 3.32 (s, 3H), 1.1-1.25 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Cl)=[CH:39][CH:38]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:41][C:40]3[CH:43]=[CH:44][C:37]([F:36])=[CH:38][CH:39]=3)[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: Fc1ccc(CCl)cc1
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(Cc5ccc(F)cc5)c4=O)CC3)c2cc1OC
Yield: 32 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and 4-fluorobenzyl chloride was used in place of methyl iodide. As a result, 116.9 mg (yield: 32%) of Compound 9 was obtained as pale yellow crystals.