Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([O:13][C:14]([C:16]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:19][NH:18][C:17]=1[CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:15])[CH3:12].[OH-].[Na+]>ClCCl.O>[CH2:11]([O:13][C:14]([C:16]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:19]([CH:3]=[O:4])[NH:18][C:17]=1[CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])=[O:15])[CH3:12]
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)c[nH]c1CCNC(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(CCNC(=O)OC(C)(C)C)[nH]c(C=O)c1-c1ccc(F)cc1
Temperature: -1 °C
Reaction time: 0.25 h
Yield: 84.37 %

Procedure:
A stirred solution of dichloromethane (5 ml) and N,N-dimethylformamide (0.6 ml) was added dropwise slowly with phosphorus oxychloride (0.414 ml, 4.5 mmol) under an argon atmosphere while maintaining the temperature at −0° C.˜0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at −1° C., added with the solution of 2-(2-tert-butoxycarbonylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (1.125 g, 3 mmol) in dichloromethane (3 ml) while maintaining the temperature at −10° C.˜0° C. for 1 hour. The mixture was stirred for another 2.5 hours at room temperature, added with cold water, adjusted to pH 11˜12 with 10% aqueous sodium hydroxide solution, extracted with ethyl acetate (50 ml×6), washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(2-tert-butoxycarbonylamino-ethyl)-4-(4-fluoro-phenyl)-5-formyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.02 g, 84.37%) as a red oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10](OCC)=[O:11])=[CH:8][N:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C([O-])(=O)C.[NH4+]>O1CCCC1.O>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccc(COCOC)nc1
Agent: CC(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COCOCc1ccc(CO)cn1
Temperature: -80 °C
Reaction time: 0.5 h

Procedure:
Compound (2) dissolved in tetrahydrofuran (100 ml) is added dropwise to a suspension of lithium aluminum hydride (9 g, 2.18×10−1 mol) in tetrahydrofuran (200 ml) cooled to −80° C. and maintained under an inert atmosphere. The reaction mixture is stirred at −80° C. for 30 minutes after the end of the addition. H2O (18 ml), 10% NaOH in water (23 ml), THF (200 ml) and then H2O (53 ml) are added. The temperature is then returned to room temperature, followed by addition of ammonium acetate (20 g, 2.6×10−1 mol) to the suspension. After 15 minutes, the reaction mixture is filtered through Celite and the filtrate is concentrated under vacuum. The residue is taken up in dichloromethane, the phases are separated by settling and the organic phase is dried over Na2SO4. After concentration under reduced pressure, the residue is purified by filtration through silica (eluent: 96/4 CH2Cl2/methanol). The product obtained (14.2 g) is used in the following step without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][N:10]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[N:10]1[C:11](=[O:13])[CH:12]=[C:7]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=2)[CH:8]=[N:9]1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)cnn1C1CCCCO1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)cnn1C1CCCCO1
Yield: 20.6 %

Procedure:
6-Oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-4-yl trifluoromethanesulfonate (2.47 g, 7.5 mmol) and 4-trifluoromethylphenylboronic acid (2.56 g, 15 mmol) were reacted according to the procedure of Example 31 (step a) to provide the title compound (500 mg, 20%) as a white solid: ESI MS m/z 325 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH:13]([CH3:22])[C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:22][CH:13]([S:12][C:8]1[C:6]2[N:7]=[C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1
Reactant: C1CNCCN1
Reactant: CSc1ccc(C(C)Sc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Product: CSc1ccc(C(C)Sc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(α-methyl-4-methylthiobenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 146°-149° C.) and piperazine.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][O+:7]([CH3:9])C.CO[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[N:13]=1.N1C=CC=CC=1.F[B-](F)(F)F>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:12][N:13]1[C:6]([O:7][CH3:9])=[CH:17][CH:16]=[CH:15][CH:14]1[CH:18]=[O:19]
Reactant: C[O+](C)C
Reactant: COc1cccc(C=O)n1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1=CC=CC(C=O)N1C

Procedure:
A 3 mL glass vial was equipped with a rubber septum and magnetic stir bar. The vial was brought into a glove box and charged with trimethyloxonium tetrafluoroborate (198 mg, 1.33 mmol). The vial was sealed and removed from the glove box. A separate 3 mL vial was charged with 2-methoxy-6-pyridinecarboxaldehyde (Aldrich #662933, 184 mg, 1.34 mmol) and was dissolved in CH2Cl2 (1.5 mL). The solution of pyridine was added via syringe onto the solid trimethoxonium tetrafluoroborate at room temperature. The vial which contained the pyridine was rinsed with CH2Cl2 (1 mL) and the rinse solution was injected into the reaction vial. The reaction vial was kept at room temperature and stirring was maintained at ca. 400-600 rpm. Over the course of the reaction (17 h), the solid trimethoxonium tetrafluoroborate gradually dissolved, the solution clarified, and an oil gradually formed. At the end of the reaction, hexanes (2 mL) were added after which stirring was stopped. Any solid or oil was allowed to settle and the solvent was removed by glass pipette. The solid or oil was then rinsed with several portions of hexanes followed by diethyl ether. Residual solvent was then removed in vacuo to provide the compound N-methyl-6-methoxy-2-pyridinecarboxaldehyde tetrafluoroborate. This oil was used for oxime formation without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 5 h
Yield: 96 %

Procedure:
tert-Butyl 4-(3-methoxy-4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (I25) (5.609 g, 16.78 mmol) was dissolved in 1:1 ethanol:ethyl acetate (500 mL) and Pd/C (2.50 g) was added. The mixture was stirred vigorously under hydrogen for five hours then filtered through celite. The celite was washed with ethyl acetate (500 mL) and the combined filtrates evaporated to give the title compound (I26) (4.93 g, 96% yield) as an off-white solid; 1H NMR (400 MHz, CDCl3) δ 6.69-6.60 (m, 3H), 4.22 (s, 2H), 3.84 (s, 3H), 2.78 (t, J=12.4 Hz, 2H), 2.54 (tt, J=12.1, 3.5 Hz, 1H), 1.80 (d, J=13.1 Hz, 2H), 1.65-1.53 (m, 2H), 1.48 (s, 9H). LCMS Method C: rt 4.91 min; m/z 251.1 [M-tBu+2H]+, 207.2 [M-Boc+2H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH2:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.Br[C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH:21]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccccc1-c1cccn2nc(N)nc12
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: COc1ccccc1-c1cccn2nc(Nc3cccc(N4CCN(C)CC4)c3)nc12

Procedure:
[8-(2-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.312 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (90.0 mg, 0.353 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (34.0 mg, 0.0622 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a pale yellow foam (0.069 g, 53%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.40 (d, J=6.5 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.54 (d, J=7.3 Hz, 1H), 7.43-7.35 (m, 2H), 7.19 (d, J=7.9 Hz, 1H), 7.11-7.02 (m, 2H), 6.94-6.89 (m, 2H), 6.79 (s, 1H), 6.55 (d, J=7.9 Hz, 1H), 3.81 (s, 3H), 3.27-3.22 (m, 4H), 2.60-2.55 (m, 4H), 2.36 (s, 3H). MS=415 (MH)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.Cl.[N:45]1[CH:50]=[CH:49][C:48]([CH2:51][C:52](O)=[O:53])=[CH:47][CH:46]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:52](=[O:53])[CH2:51][C:48]3[CH:49]=[CH:50][N:45]=[CH:46][CH:47]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)Cc1ccncc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccncc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (1.2 g, 7.8 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 4-pyridylacetic acid hydrochloride (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 3:97) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-pyridin-4-yl-acetamide (0.4 g, 50%) as white solid: mp 294-296° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=0.87 min. (98%); 1H NMR (DMSO-d6) δ 2.02-2.07 (m, 1H), 2.52-2.96 (m, 2H), 2.84-2.96 (m, 1H), 3.59 (s, 2H), 5.12-5.18 (dd, J=5.2 and 12.7 Hz, 1H), 7.31 (d, J=5.5 Hz, 2H), 7.64-7.70 (m, 1H), 7.79-7.84 (m, 2H), 8.50 (d, J=5.6 Hz, 2H), 8.77 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 37.91, 41.27, 48.83, 121.96, 124.54, 127.17, 131.53, 133.30, 134.71, 138.88, 144.92, 149.37, 166.88, 167.41, 169.33, 169.78, 172.73; Anal. Calcd. for C21H18N4O5: C, 62.07; H, 4.46; N, 13.79. Found: C, 61.77; H, 4.39; N, 13.59.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[C:14]1([CH:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[N:15]=[N:16][N:17]2[C:22]=1[C:21]1[CH:23]=[CH:24][NH:25][C:20]=1[N:19]=[CH:18]2.O>O1CCCC1>[C:14]1([CH:26]2[CH2:31][CH2:30][C:29](=[CH:3][C:1]#[N:2])[CH2:28][CH2:27]2)[N:15]=[N:16][N:17]2[C:22]=1[C:21]1[CH:23]=[CH:24][NH:25][C:20]=1[N:19]=[CH:18]2
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
Diethyl (cyanomethyl)phosphonate (37.0 μL, 0.235 mmol) in tetrahydrofuran (1 mL) was mixed with sodium hydride (55 wt % dispersion in mineral oil, 10.0 mg, 0.235 mmol) under cooling with ice and then stirred for 30 minutes. The reaction mixture was mixed with 4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanone (20.0 mg, 0.0783 mmol) obtained in Synthetic Examplea 82 and then stirred at room temperature for 30 minutes. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2→1/1→1/0 (v/v)) to give the title compound as a colorless solid (20.0 mg, yield 92%).
Reaction SMILES: [CH3:1][CH:2](O)[CH2:3][C:4]#[CH:5].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:5][CH:4]([N:11]1[C:7](=[O:17])[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:12])[CH2:3][C:2]#[CH:1]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C#CCC(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CCC(C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.4 %

Procedure:
400 ml of dry tetrahydrofuran, 5.00 g of 4-pentin-2-ol, 9.65 g of phthalimide, and 17.13 g of triphenylphosphine were added to a nitrogen-substituted flask. Thereafter, 30 ml of diethyl azodicarboxylate (40% toluene solution) was slowly added dropwise to the obtained solution at a room temperature, and the obtained mixture was then stirred at a room temperature for 1 day. Thereafter, the reaction solution was concentrated, and 300 ml of water was then added to the residue, followed by extraction with 250 ml of ethyl acetate twice. The organic layer was washed with 200 ml of water and then with 200 ml of a saturated brine. The resultant was dried over magnesium sulfate. The magnesium sulfate was filtrated, and the organic layer was then concentrated. The residue was then purified by column chromatography (Wako Gel C-200; toluene), so as to obtain 2.20 g of a phthalimide compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:43]([NH:50][C:51]([NH2:53])=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[CH2:43]([NH:50][C:51](=[O:52])[NH:53][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: CCOC(=O)CCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NCCc1[c-]cccc1
Solvent: C1COCCO1
Product: CCOC(=O)CCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)NCc3ccccc3)ncc12
Temperature: 100 °C
Yield: 52.9 %

Procedure:
An oven-dried, nitrogen cooled 2 ml microwave vial was charged with ethyl 3-(6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)propanoate (59 mg, 0.119 mmol), BrettPhos precatalyst (5 mg, 6.26 μmol), cesium carbonate (122 mg, 0.374 mmol) and 1-benzylurea (32 mg, 0.213 mmol), sealed under a nitrogen atmosphere, charged with Dioxane (0.5 ml) and heated to 100° C. for 16 hr. Filtered through celite, eluted with EtOAc, concentrated in vacuo and purified via flash chromatography (0-20% MeOH/DCM) to provide ethyl 3-(6-(3-benzylureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)propanoate (38.7 mg, 0.063 mmol, 53.4% yield) as a yellow solid. MS ESI calc'd for C38H35N5O3 [M+H]+=610, found 610.
Reaction SMILES: [ClH:1].[O:2](CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:3]1C=CC=C[CH:4]=1.Cl.[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47](C(C)(C)C)=[CH:46][CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.Cl.O[C@H](COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([O:2][CH2:3][CH3:4])=[CH:46][CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: CCOc1ccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 358 (M-15,.1), 253 (17), 252 (100), 163 (6), 121 (21), 114 (8), 108 (8).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:28]([O-])([N+]([O-])=O)=[O:29]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 77.9 %

Procedure:
3.3 g of 1-(2-chloroethyl)-3-n-propyl-3-D-galactopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.8 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-D-galactopyranosylurea are thereby obtained as pale yellow caramel. [α]D23 +18.0°(C=1.0, methanol)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=O)=[C:8]([CH3:15])[CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[NH2:27])[C:21]([OH:23])=[O:22]>CS(C)=O>[CH3:1][O:2][C:3]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:18]3[CH:19]=[C:20]([C:21]([OH:23])=[O:22])[CH:24]=[CH:25][C:26]=3[N:27]=2)=[C:8]([CH3:15])[CH:7]=1)=[O:16]
Reactant: COC(=O)COc1cc(C)c(C=O)c(C)c1
Reactant: Nc1ccc(C(=O)O)cc1N
Solvent: CS(C)=O
Product: COC(=O)COc1cc(C)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Reaction time: 8 h

Procedure:
To a solution (4-formyl-3,5-dimethylphenoxy)-acetic acid methyl ester (2.4 g) (from Example 6-9) and 3,4-diaminobenzoic acid (2.0 g) in DMSO (30 mL) under air at ambient temperature was added FeCl3 (150 mg) and the resulting brown reaction mixture was stirred at the same temperature overnight. The reaction was monitored by LC/MS which indicated completion. The reaction mixture was then decanted into 400 mL of stirred water and the resulting precipitate was collected by filtration and washed with water. The crude product was dried in the suction funnel for 4 h to give 2-(4-methoxycarbonylmethoxy-2,6-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid. MS (ESI) m/z 355.04 (M+H); Retention time=0.79 min (Method 10).
Reaction SMILES: C(OCC=C)C=C.[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>C(OCCOCCO)C>[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:24]([C:25]1([CH2:26][CH:27]=[CH2:28])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:29][CH2:30]1)[CH:23]=[CH2:22]
Reactant: c1ccc2c(c1)CCC2
Agent: C=CCOCC=C
Solvent: Oc1ccccc1
Solvent: CCOCCOCCO
Product: C=CCC1(CC=C)CCc2ccccc21
Yield: 75 %

Procedure:
140 grams of the diallyl ether of indane bisphenol was placed into a one liter round bottom flask containing a magnetic stir bar and dissolved in 210 grams of 2-(2-ethoxyethoxy) ethanol. The solution was deoxygenated by bubbling dry argon gas through the solution for 15 minutes, and then a reflux condenser was attached. The solution was refluxed for 6 hours under an inert atmosphere. The solvent was removed by vacuum distillation between 60° and 62° C., and the product was collected between 210° and 214° C. as a light yellow, viscous liquid (13.3 Pa). Diallyl indane bisphenol was so viscous that the condenser on the still has to be heated with a hot air gun so that the product could flow into the collection flask; 110 grams of diallyl indane bisphenol were isolated (75% yield overall).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8](C)[C:9](OC)=[C:10](C)[CH:11]=2)[CH:6](C)[CH2:5]1)(=O)C.C([BH-](CC)CC)C.[Li+].[O:26]1CCC[CH2:27]1>>[CH3:27][O:26][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COc1c(C)cc2c(c1C)C(C)CN2C(C)=O
Reactant: C1CCOC1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Product: CON1CCc2ccccc21
Temperature: 0 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
To an ice-cold solution of indoline 9 (377 mg, 1.6 mmol) dissolved in tetrahydrofuran (5 mL) and kept under an argon atmosphere was added lithium triethylborohydride (3.2 mL, 3.2 mmol), and the mixture was stirred over the range of 0° C. to room temperature for 20 h. The reaction mixture was quenched with 3N hydrochloric acid, and volatiles were removed under vacuum. The resulting solution was acidified to pH 2 with additional 3N hydrochloric acid and washed with methylene chloride. The aqueous solution was basified with saturated aq. sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine and dried (MgSO4). Removal of solvents gave crude methoxyindoline (200 mg, 65% yield) as a brownish yellow oil, which was used without further purification.
Reaction SMILES: [NH:1]([CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C>CN(C)C=O.O>[C:24]([O:28][C:29](=[O:30])[NH:31][CH2:32][C:33](=[O:34])[N:1]([CH2:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(CNc1ccccc1)Nc1ccc(-c2ccncc2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N(CC(=O)Nc1ccc(-c2ccncc2)cc1)c1ccccc1
Reaction time: 24 h
Yield: 48.1 %

Procedure:
To a mixture of 2-anilino-N-[4-(4-pyridinyl)phenyl]acetamide (50.0 mg) and [(tert-butoxycarbonyl)amino]acetic acid (86.6 mg) in N,N-dimethylformamide (1.0 mL) were added diisopropylethylamine (0.189 mL) and N-[(dimethylamino) (3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate (207 mg) at ambient temperature and the mixture was stirred at the same temperature for 24 hours. Water (3.0 mL) was added to the mixture and the resulting mixture was extracted with ethyl acetate (6.0 mL). The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (10% methanol in chloroform) to afford tert-butyl{2-oxo-2-[(2-oxo-2-{[4-(4-pyridinyl)phenyl]amino}ethyl)(phenyl)amino]ethyl}carbamate (36.5 mg) as yellow crystals.