Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]1([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:6][C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3]1.CI.[H-].[Na+].[C:28](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:28][N:16]([C@@:2]1([CH3:1])[CH2:6][C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH2:3]1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@H](c1ccccc1)N1C[C@@](C)(NC(=O)OC(C)(C)C)CC1=O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C[C@@](C)(N(C)C(=O)OC(C)(C)C)CC1=O
Reaction time: 1 h
Yield: 96 %

Procedure:
Tert-Butyl {(3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl}carbamate (I-343) (4.08 g, 12.8 mmol) and methyl iodide (1.20 ml, 19.2 mmol) were dissolved in N,N-dimethylformamide (120 ml), and with cooling with ice, sodium hydride (55% w/w) (671 mg, 15.4 mmol) was added, followed by stirring for 1 hour with cooling with ice. With cooling with ice, aqueous 10% citric acid solution was added to the reaction liquid, followed by concentration under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate, then the insoluble was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1→1:4, v/v) to obtain tert-butyl methyl-{(3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl}carbamate (4.09 g, 96%) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[CH3:47][C:48]1[O:52][N:51]=[C:50]([C:53](Cl)=[O:54])[CH:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:53]([C:50]2[CH:49]=[C:48]([CH3:47])[O:52][N:51]=2)=[O:54])[CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCNC1
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCCC(C(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)C2)no1
Yield: 62 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 62% yield. LCMS for C29H29ClN7O3 (M+H)+: m/z=558.2.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].[F:9][CH:10]([C:15](OC)=[O:16])[C:11](OC)=[O:12]>CO>[F:9][C:10]1[C:11]([OH:12])=[N:7][C:5]([CH3:6])=[N:8][C:15]=1[OH:16]
Reactant: CC(=N)N
Reactant: COC(=O)C(F)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1nc(O)c(F)c(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.2 %

Procedure:
A solution of 200 mL of 25% wt sodium methoxide in methanol (0.84 mol) was diluted with an additional 200 mL of methanol. Acetamidine-HCl (40 g, 0.42 mol) was added to the sodium methoxide solution (white precipitate formed), followed by addition of dimethyl fluoromalonate (70 g, 0.46 mol). The contents were stirred at room temperature overnight, then concentrated in vacuo to dryness. The resulting residue was redissolved in hot water (300 mL). After cooling the aqueous solution to room temperature, concentrated HCl was added slowly until crystal formation (fine white prisms) took place at about pH 5. Concentrated HCl was added dropwise until pH 3, and then the contents were filtered. The isolated crystals were rinsed with 1M HCl and dried under vacuum to provide 5-fluoro-4,6-dihydroxy-2-methylpyrimidine (65.5 g, >100%). LCMS: (M+H)+: 145.
Reaction SMILES: C[Sn](C)(C)[C:3]1([F:18])[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])=[CH:5][CH:4]1[F:17].[CH3:21][C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][N:28]=2)=[N:25][N:26]=1>>[CH3:21][C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:3]3([F:18])[CH:8]=[CH:7][C:6]([N:9]4[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]4=[O:16])=[CH:5][CH:4]3[F:17])=[CH:29][N:28]=2)=[N:25][N:26]=1
Reactant: Cc1nnc(-c2ccc(Br)cn2)o1
Reactant: C[Sn](C)(C)C1(F)C=CC(N2C[C@H](CO)OC2=O)=CC1F
Product: Cc1nnc(-c2ccc(C3(F)C=CC(N4C[C@H](CO)OC4=O)=CC3F)cn2)o1

Procedure:
The same procedure as in Example 1 was conducted by using (R)-3-(4-trimethylstannyl-3,4-difluorophenyl)-2-oxo-5-oxazolidinylmethanol and 2-(2-methyl-[1,3,4]oxadiazol-5-yl)-5-bromopyridine as a starting material, to prepare the title compound.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)=[O:15]>>[OH:15][N:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)(C)NCc1ccccc1
Product: CC(C)(C)N(O)Cc1ccccc1
Yield: 99.6 %

Procedure:
A solution of 0.057 M DMD in acetone (47.4 ml, 2.7 mmol) was added to a cold stirred solution of N-tert-butyl-N-benzylamine (Aldrich, 0.4417 g, 2.7 mmol) in acetone (5 ml). The reaction mixture was stirred for fifteen minutes in an ice bath. Solvent was removed on a rotary evaporator to give a white, microcrystalline solid (0.4803 g, 99.6% yield), mp 58-60. Flash chromatography of the solid over silica gel and elution with a 90:10 mixture of petroleum ether (bp 35-60) and ethyl acetate gave the hydroxylamine as a white crystalline solid, mp 60-61.5 (reported mp 71-73, Emmons 1957). Distillation of this material gave a solid with the same mp.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([O:27]C)=O)[CH3:9].[NH3:29]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([NH2:29])=[O:27])[CH3:9]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OC(C)c1ccccc1Cl
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cnccc32)sc1C(N)=O)c1ccccc1Cl
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 87 mg of the above-synthesized methyl 3-[1-(2-chlorophenyl)ethoxy]-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and 10 ml of a saturated solution of ammonia in methanol was stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture was allowed to cool down to room temperature, then another 10 ml of a saturated solution of ammonia in methanol were added and the procedure was repeated as described above. The solvent was removed under vacuum and the residue was purified by flash chromatography to yield the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13](=[CH2:16])[CH2:14][SH:15].C(N(CC)CC)C>O1CCCC1>[CH3:16][C:13](=[CH2:12])[CH2:14][S:15][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: C=C(C)CS
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)CSc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of 5.0 g (0.031 mole) of 2,4-difluoronitrobenzene and 2.8 g (0.031 mole) of 2-methyl-2-propenethiol in 25 ml of tetrahydrofuran at room temperature was added dropwise 3.1 g (0.031 mole) of triethylamine. The reaction mixture was stirred at room temperature for forty-eight hours and then at 50° C. for eight hours. The tetrahydrofuran was removed under reduced pressure, and water was mixed with the residue. This aqueous mixture was extracted with chloroform. The chloroform extract was washed with water, dried, and the chloroform evaporated under reduced pressure, leaving an oily residue. Distillation of this residue under reduced pressure yielded 6.0 g of 2-(2-methyl-2-propenylthio)-4-fluoronitrobenzene. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:8][C:9](=[O:48])[C@H:10]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37]C(OCC1C=CC=CC=1)=O)[NH:11][C:12](=[O:32])[CH2:13][CH2:14][C@H:15]([C:29](=[O:31])[NH2:30])[NH:16][C:17](=[O:28])[C@H:18]([CH3:27])[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[C:23]([O:22][C:20]([NH:19][C@H:18]([C:17]([NH:16][C@@H:15]([C:29](=[O:31])[NH2:30])[CH2:14][CH2:13][C:12]([NH:11][C@H:10]([C:9]([OH:48])=[O:8])[CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[O:32])=[O:28])[CH3:27])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(N)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)N[C@@H](CCCCN)C(=O)O)C(N)=O
Yield: 89.1 %

Procedure:
In 40 ml of acetic acid was dissolved 4.00 g of Nα -(t-butyloxycarbonyl-alanyl-D-isoglutaminyl)-Nε -benzyloxycarbonyl-lysine benzyl ester, and the solution was hydrogenolyzed in the presence of palladium-on-carbon in a hydrogen stream at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated. To the residue was added diethyl ether, and the precipitated powder was recrystallized from methanoldiethyl ether to obtain 2.37 g of Nα -(t-butyloxycarbonylalanyl-D-isoglutaminyl)-lysine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH3:8].F[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>CC(N(C)C)=O>[CH3:8][CH:3]1[N:2]([CH3:1])[CH2:7][CH2:6][N:5]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:4]1
Reactant: CC1CNCCN1C
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N2CCN(C)C(C)C2)cc1
Temperature: 150 °C
Yield: 32.5 %

Procedure:
1,2-Dimethylpiperazine (2.284 g, 20.00 mmol) and ethyl 4-fluorobenzoate (1.467 mL, 10 mmol) were dissolved in DMA (12 mL) and sealed in a microwave tube. The reaction was heated to 150° C. for 90 mins in the microwave reactor and cooled to room temperature. The reaction mixture was heated for a further 30 mins at 150° C. and cooled to room temperature. The reaction mixture was evaporated and the crude product was purified by silica column chromatography, eluting with 5% MeOH in DCM with 0.1% 0.880 ammonia. Pure fractions were evaporated to dryness to afford ethyl 4-(3,4-dimethylpiperazin-1-yl)benzoate (0.853 g, 32.5%) as a colourless waxy solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:28]=[C:29]([NH2:34])[CH2:30][CH2:31][O:32][CH3:33]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:25][N:34]=[C:29]([CH2:30][CH2:31][O:32][CH3:33])[N:28]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: COCCC(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(CCOC)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
60 mg (0.17 mmol) of the compound from Example 59A and 30 mg (0.25 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 32 mg (44% of theory)
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[C:6]([CH2:8]O)[CH:7]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]C(Br)(Br)Br>C1COCC1>[Br:29][CH2:8][C:6]1[CH:7]=[C:3]([C:1]#[N:2])[S:4][CH:5]=1
Reactant: N#Cc1cc(CO)cs1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cc(CBr)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.7 %

Procedure:
11.7 g (84.07 mmol) of 2-cyano-4-hydroxymethylthiophene together with 24.1 g (91.87 mmol) of triphenylphosphine were dissolved in 100 ml of-THF at room temperature, and 30.47 g (91.87 mmol) of tetrabromomethane were added, a little at a time, with cooling (ice bath). After stirring for 3 hours at room temperature, the mixture was concentrated in vacuo and purified by chromatography over silica gel (methylene chloride/petroleum ether). 18.8 g of crystalline pale yellow product which still contained petroleum ether resulted.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH2:8][CH2:9][CH2:10][N:11]([C:14]1[N:23]=[C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:35]#[N:36])[CH:20]=2)[N:15]=1)OC)=[O:7])C.Cl.[CH2:38](O)C>>[C:6]([CH2:8][CH2:9][CH2:10][N:11]([C:14]1[N:23]=[C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:35]#[N:36])[CH:20]=2)[N:15]=1)[CH3:38])([OH:5])=[O:7]
Reactant: CCO
Reactant: CCOC(=O)CCCN(OC)c1nc(NCc2ccc3c(c2)OCO3)c2cc(C#N)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(CCCC(=O)O)c1nc(NCc2ccc3c(c2)OCO3)c2cc(C#N)ccc2n1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
20 ml of ethanol and 2.61 ml of a 1N aqueous solution of sodium hydroxide were added to 389 mg of 2-[N-(3-ethoxycarbonylpropyl)-N-methoxyamino]-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was stirred at room temperature for 4 hours and at 50° C. for 10 minutes and neutralized with 1N hydrochloric acid. The crystals precipitated were recovered by filtration, purified by silica gel column chromatography (chloroform/methanol) and recrystallized from ethanol/acetone/water to give 305 mg of the title compound.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1CO>C(Cl)Cl>[Br:5][CH2:1][C:27]1[CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=[CH:31][C:26]=1[I:25]
Reactant: OCc1cc(C(F)(F)F)ccc1I
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(I)c(CBr)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Carbon tetrabromide (1.86 g; 5.6 mmol) and triphenylphosphine (1.47 g; 5.6 mmol) were added successively to a stirred solution of [2-iodo-5-(trifluoromethyl)phenyl]methanol (Intermediate 10, 1.13 g; 3.74 mmol) in CH2Cl2 (25 mL) at 0° C. under N2. The reaction was stirred at room temperature for 48 h. A second equivalent of carbon tetrabromide (1.2 g; 3.74 mmol) and triphenylphosphine (0.98 g; 3.74 mmol) was added and the reaction was stirred an additional 14 h. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (0-25% EtOAc/hexanes gradient) to afford 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene as a clear oil. 1H NMR (CDCl3, 500 MHz): δ 8.02 (d, J=8.2 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.26 (dd, J=8.3, 1.8 Hz, 1H), 4.64 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][C:8]#[N:9])([O-:3])=[O:2].O.[C:14]([OH:18])(=[O:17])[CH:15]=O.C(=O)([O-])[O-].[K+:23].[K+]>CO>[K+:23].[C:8]([C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[CH:15][C:14]([O-:18])=[O:17])#[N:9]
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Reactant: O=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CC(=CC(=O)[O-])c1cccc([N+](=O)[O-])c1
Reaction time: 5 h
Yield: 85.1 %

Procedure:
A suspension of 3-nitrobenzyl cyanide (1.62 g), glyoxylic acid monohydrate (1.38 g) and potassium carbonate (3.59 g) in methanol (20 ml) was stirred for 5 hours. The precipitate was collected by filtration, washed with dichloromethane and dried. The precipitate was suspended in water and stirred for an hour. The insoluble material was collected by filtration and dried to give 3-cyano-3-(3-nitro-phenyl)-acrylic acid potassium salt (2.18 g, 85.2%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[CH2:15]([O:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27](=O)[C:28](OC)=[O:29])=[CH:23][NH:24]2)=[CH:20][CH:19]=1)[CH3:16].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH2:15]([O:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27]3[C:28](=[O:29])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:23][NH:24]2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: CCOc1ccc2c(C(=O)C(=O)OC)c[nH]c2c1
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c[nH]c2c1
Temperature: 70 °C
Yield: 25.7 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (381 mg, 2.02 mmol) and methyl 2-(6-ethoxy-1H-indol-3-yl)oxoacetate (500 mg, 2.02 mmol) in DMF (17 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (2.0 mL, 2.0 mmol) at 4° C. under N2. The reaction was stirred for 20 min at this temperature, and additional potassium tert-butoxide (1.0 M, 4.1 mL, 4.1 mmol) was added. The resulting dark purple solution was heated up to 70° C. over night. The mixture was cooled to 4° C. and quenched with 1.0 N hydrochloric acid (12 mL) and poured into EtOAc (500 mL). The organic layer was separated, dried (MgSO4), and concentrated to a red solid. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (200 mg, 26%) as a red solid, mp 212–215° C. 1H NMR (CDCl3) δ 8.44 (s, 1H), 7.88 (s, 1H), 7.68 (m, 1H), 7.60 (s, 1H), 7.00 (m, 2H), 6.92 (s, 1H), 6.72 (s, 1H), 6.52 (s, 1H), 6.32 (s, 2H), 3.92 (q, J=6.5 Hz, 2H), 3.72 (s, 3H), 1.38 (t, J=6.5 Hz, 3H). MS (ESI, Negative Mode): m/z=384 [C23H19N3O3−H]−
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[C:1]([CH:11]=[O:12])=[CH:2][CH:3]=[CH:4]2
Reactant: BrBr
Reactant: O=Cc1cccc2ccccc12
Solvent: ClC(Cl)Cl
Product: O=Cc1cccc2cc(Br)ccc12
Yield: 36.7 %

Procedure:
To a flask fitted with a condenser containing 1-naphthaldehyde (10 g, 64.02 mmol) was added a solution of bromine (3.3 mL, 63.83 mmol) in anhydrous chloroform (15 mL). The reaction mixture was heated under reflux for 3.5, allowed to RT and filtered. The filtrate was washed with water, brine and dried (MgSO4). After evaporation the crude product was purified on silica gel (eluant: hexanes:EtOAc, 98:2) to afford 6-bromo-1-naphthaldehyde 5.5 g (27%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10](Br)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>C1COCC1>[C:1]([O:5][C:6](=[O:16])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([Si:23]([CH3:25])([CH3:24])[CH3:22])[CH:9]=1)[Si:23]([CH3:25])([CH3:24])[CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Br
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(N(C(=O)OC(C)(C)C)[Si](C)(C)C)cc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a stirred solution of tert-butyl(3-bromo-4-methylphenyl)carbamate (2.86 g, 10 mmol) in THF (20 mL) was added n-BuLi (2.5 M in hexanes, 8.8 mL, 22 mmol) at −78° C. and the solution was stirred at this temperature for another 30 min. Trimethylsilyl chloride (2.39 g, 22 mmol) was added at −78° C. and the reaction mixture was then allowed to warm up to r.t. and stirred at r.t. for 1 hr. The reaction was quenched with H2O. EtOAc and more water were added for extraction. The combined organic layer was dried (Na2SO4), filtered, concentrated, and the resulting residue was purified by silica gel flash chromatography (eluted with 20% EtOAc in Hexanes) to give the desired product as a white solid (3.33 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH2:24][CH:25]=[CH2:26])[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH2:24][CH:25]3[O:36][CH2:26]3)[C:20]([O:22][CH3:23])=[O:21])(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: C=CCC(NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)C(=O)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonylamino]-pent-4-enoate 1(15.3 g, 40.8 mmol) in CH2Cl2(150 mL), NaHCO3 (7.1 g, 85 mmol) and water (80 mL) at 0° C., is added slowly m-chloroperbenzoic acid (32.6 g, ˜123 mmol, 57-86%). The reaction mixture is stirred overnight. The reaction is then diluted with aqueous NaHCO3 and the mixture is extracted three times with EtOAc. The combined EtOAc layer is washed with NaHCO3, brine, dried over MgSO4 and concentrated to an oil. Purification is accomplished by column chromatography with EtOAc/hexane (3:7 to 6:4) as the eluent to give the desired product as a mixture of two isomers (ratio 2:3).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(=O)OC(C)(C)C)c2ccccc2n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1cc(CBr)nc2ccccc12
Temperature: 90 °C
Reaction time: 5 h
Yield: 42.9 %

Procedure:
To a mixture of tert-butyl 2-methylquinoline-4-carboxylate (4.61 g) and carbon tetrachloride (50.0 mL) were added N-bromosuccinimide (3.71 g) and azobisisobutyronitrile (156 mg), followed by stirring at 90° C. for 5 hours. The reaction suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 2-(bromomethyl)quinoline-4-carboxylate (2.62 g).
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: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: COc1ccc(C=O)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).