Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:15])[C:6]([F:8])([F:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13]O)[C:4]=2[O:3]1.[Br-:16].[Li+].C[Si](Cl)(C)C>C(#N)C>[F:1][C:2]1([F:15])[C:6]([F:8])([F:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][Br:16])[C:4]=2[O:3]1
Reactant: OCc1cccc2c1OC(F)(F)C2(F)F
Reactant: [Br-]
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: CC#N
Product: FC1(F)Oc2c(CBr)cccc2C1(F)F

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 5, using 11.1 grams (0.05 mole) of 2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethanol, 8.7 grams (0.1 mole) of lithium bromide, and 13.5 grams (0.125 mole) of trimethylsilyl chloride in 100 mL of acetonitrile, yielding 2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethyl bromide.
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.[CH2:6]([C:9]1[C:10]([NH:35][C@H:36]2[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]2)=[N:11][C:12]2[N:13]([N:32]=[CH:33][CH:34]=2)[C:14]=1[N:15]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=1)[CH:7]=[CH2:8].[H-].[Na+].C(Br)C=C>O.CN(C)C=O>[CH2:4]([N:35]([C:10]1[C:9]([CH2:6][CH:7]=[CH2:8])=[C:14]([N:15]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH3:24])=[CH:20][CH:21]=2)[N:13]2[N:32]=[CH:33][CH:34]=[C:12]2[N:11]=1)[C@H:36]1[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[CH2:37]1)[CH:3]=[CH2:2]
Reactant: C1CCOC1
Reactant: C=CCc1c(N[C@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2ccnn2c1N(C(=O)OC(C)(C)C)c1ccc(OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C=CCBr
Product: C=CCc1c(N(CC=C)[C@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2ccnn2c1N(C(=O)OC(C)(C)C)c1ccc(OCC)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a mixed solution of tetrahydrofuran (0.6 mL) and N,N-dimethylformamide containing tert-butyl (S)-3-{6-allyl-7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]pyrazolo[1,5-a]pyrimidin-5-ylamino}piperidine-1-carboxylate (100 mg, 0.168 mmol), sodium hydride and allyl bromide were added at 0° C., and the mixture was stirred at 70° C. for 5 hr. To the reaction solution, water was added, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound (102 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=2[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:6](=[O:9])[CH2:7][N:8]=1.CC(C)([O-])C.[K+].N1C2C=CC=CC=2C=CC=N1.[Cl:41][C:42]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:43]=1[CH2:44]Br>O1CCCC1>[Cl:1][C:2]1[C:3]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=2[N:5]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:6](=[O:9])[CH:7]([CH2:44][C:43]2[CH:46]=[CH:47][C:48]([F:50])=[CH:49][C:42]=2[Cl:41])[N:8]=1
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: COc1ccc(CN2C(=O)CN=C(Cl)c3cc(Cl)ccc32)cc1
Agent: C1=Cc2ccccc2NN=C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(Cc3ccc(F)cc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 33.5 %

Procedure:
5,7-Dichloro-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.85 g, 3.82 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and cooled to −78° C. under nitrogen. Potassium tert-butoxide (0.48 g, 3.82 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL) and added to the benzodiazepine via syringe. After 2 minutes, a solution of the 2-chloro-4-fluorobenzyl bromide (1.27 g, 3.64 mmol) in anhydrous tetrahydrofuran (3 mL) was added. The reaction mixture was stirred at −78° C. for 2 then allowed to warm to room temperature over 1 h. The reaction was quenched with water and the layers partitioned. The organic layer was evaporated onto silica gel and chromatographed eluting with 10-35% ethyl acetate in hexanes to obtain 5,7-dichloro-3-(2-chloro-4-fluorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.6 g, 1.22 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[N:31][C:32]=2[Cl:34])[N:27]([CH3:35])[N:26]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([CH:14]=1)[O:15][CH2:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[N:31][C:32]=2[Cl:34])[N:27]([CH3:35])[N:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1O
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(OCc2ccccc2)cc1OCc1nn(C)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-benzyloxy-2-methyl-phenol (83.4 mg, 0.389 mmol, 37009-93A) and potassium carbonate (61.8 mg, 0.438 mmole) was stirred at room temperature for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (89.8 mg, 0.344 mmole, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was either used directly in the next step or purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give pure 3-(5-benzyloxy-2-methyl-phenoxymethyl)-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 48.0 mg).
Reaction SMILES: COC([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([N+]([O-])=O)=[CH:10][C:8]=2[CH:9]=1)=O.[O-]S([O-])(=O)=O.[Na+].[Na+]>CO.[Pd]>[O:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=[CH:5]1
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: c1ccc2occc2c1
Reaction time: 72 h

Procedure:
A suspension of 2-methoxycarbonyl-5-nitrobenzofuran (2.0 g), 10% Pd/C (2.0 g), Na2SO4 (2.0 g) in MeOH (500 mL) was hydrogenated at 55 PSI for 3 days. The resulting solution was filtered through a pad of celite, concentrated and chromatographed using n-hexanes then 10%, 20% EtOAc/n-hexanes to give (±)-5-amino-2,3-dihydro-2-methoxycarbonyl)benzofuran. 1H NMR (CDCl3): δ 6.69 (d, 1H , J=8.1 Hz), 6.56 (d, 1H, J=1.2 Hz), 6.48 (dd, 1H, J=1.8 and 7.5 Hz), 5.14 (dd, 1H, J=6.6 and 7.2 Hz), 3.79 (s, 3H), 3.47 (dd, 1H, J=10.5 and 10.8 Hz), 3.26 (dd, 1H, J=7.2 and 6.6 Hz); LCMS: purity: 100%; MS (m/e): 194 (MH+).
Reaction SMILES: CN1CCCC(C(O)=O)C1.[CH:11]([N:14]([CH:22]([CH3:24])[CH3:23])[CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])([CH3:13])[CH3:12].[ClH:25]>>[ClH:25].[CH:22]([N:14]([CH:11]([CH3:13])[CH3:12])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])([CH3:24])[CH3:23]
Reactant: CCOC(=O)CCN(C(C)C)C(C)C
Agent: CN1CCCC(C(=O)O)C1
Agent: Cl
Product: CC(C)N(CCC(=O)O)C(C)C

Procedure:
3-Diisopropylaminopropionic acid hydrochloride may be obtained by working according to the method described in Example 4 for the preparation of 1-methyl-3-piperidinecarboxylic acid, but starting with ethyl 3-diisopropylaminopropionate (5 g) and 6N aqueous hydrochloric acid solution (35 cc). After the product obtained has been recrystallized in acetone, 3-diisopropylaminopropionic acid hydrochloride (2.3 g), m.p. 170° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14]3=[C:15]([CH2:17][CH2:18][N:13]3[C@@H:12]3[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][C@H:11]23)[CH:16]=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14]3=[C:15]([CH2:17][CH2:18][N:13]3[C@@H:12]3[CH2:19][CH2:20][NH:21][CH2:22][C@H:11]23)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccccc3Cl)cc3c1N2CC3
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccccc1-c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
Tert-butyl (±)-cis-2-(2-chlorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (45.1 mg, 0.11 mmol) was dissolved in 20% TFA in methylene chloride (4 mL) and was stirred at RT for 2 h. The reaction was solution was cooled to 0° C. and basified with 1M NaOH until pH>14. The layers were separated. The aqueous phase was extracted the methylene chloride (2×10 ml). The organic layers were washed with brine and dried. Concentration afforded the title compound (29.3 mg, 86%) as a pale yellow amorphous solid. 1H NMR (CDCl3, 300 MHz) δ7.42 (dd, 1H, J=1.4, 7.3 Hz), 7.16-7.33 (m, 3H), 7.02 (s, 1H), 6.96 (s, 1H), 3.69 (dt, 1H, J=1.4, 8.1 Hz), 3.15-3.50 (m, 5H), 3.06 (dt, 1H, J=3.2, 12.3 Hz), 2.82-2.97 (m, 3H), 1.78-1.93 (m, 2H) ppm. MS (CI, NH3): 311 (base, M+H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH:10]1([N:15]2[C:19]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:18]=3[CH:17]=[C:16]2[C:26](OC)=[O:27])[CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl.CO>[CH:10]1([N:15]2[C:19]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:18]=3[CH:17]=[C:16]2[CH2:26][OH:27])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COC(=O)c1cc2cnc(SC)nc2n1C1CCCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: ClCCl
Product: CSc1ncc2cc(CO)n(C3CCCC3)c2n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.7 %

Procedure:
DIBAL-H (1.0 M in toluene) (33.8 mL, 33.8 mmol) was added dropwise to a solution of compound 227 (4.93 g, 16.9 mmol) in dichloromethane (85 mL) at −78° C. The reaction was stirred for 20 minutes, then warmed to 0° C. and quenched with 400 mL of 0.5 M Rochelle's salt saturated with NaCl. The mixture was stirred for 3 h then extracted with ethyl acetate (4×250 mL). The combined organics were washed with brine, dried over MgSO4, and concentrated in vacuo to provide 4.36 g of crude. The crude material was taken up in dichloromethane and methanol, plated onto silica gel, and flashed through a plug of silica using 30% ethyl acetate in hexanes, then switching to 10% methanol in DCM to provide compound 228 (3.37 g, 75.6% yield). 1H NMR (500 MHz, CDCl3) δ 8.60 (s, 1 H) 6.29 (s, 1 H) 4.83-4.95 (m, J=17.30, 8.59, 8.59 Hz, 1 H) 4.79 (d, J=5.87 Hz, 2 H) 2.62 (s, 3 H) 2.47-2.58 (m, 2 H) 1.97-2.15 (m, 5 H) 1.67-1.81 (m, 2 H) ppm.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)#[N:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(Cl)Cl>[CH2:14]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[C:3]([C:1]#[N:2])=[C:4]1[C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[O:21])=[CH:18][CH:17]=1)[CH3:15]
Reactant: CCn1c(-c2ccc(C(=O)O)cc2)c(C#N)c2ccc(OC)cc21
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1c(-c2ccc(C(=O)N3CCOCC3)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (50 mg, 0.16 mmol) was suspended in CH2Cl2 (2.2 mL) and catalytic DMF (2 μL). Oxalyl chloride (22 μL, 0.25 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, at which time full dissolution occurred. This reaction mixture was pipetted dropwise into a vigorously stirring solution of morpholine (1.0 mL) in CH2Cl2 (5 ml). After addition was complete, the reaction mixture was washed with aqueous HCl solution. The organic layer was dried and concentrated. Purification by silica column (1:1 CH2Cl2/EtOAc) yielded 1-ethyl-6-methoxy-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-carbonitrile (56 mg, 90%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:23])[CH2:14][CH:15]([C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:17]O)=[C:4]([F:24])[CH:3]=1.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:23])[CH2:14][CH:15]([C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:17][Cl:27])=[C:4]([F:24])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)Oc1cc(NC(=O)CC(CCO)C(F)(F)F)c(F)cc1Cl
Solvent: ClCCl
Product: CC(C)Oc1cc(NC(=O)CC(CCCl)C(F)(F)F)c(F)cc1Cl
Temperature: 40 °C
Reaction time: 64 h

Procedure:
To a solution of N-(4'-chloro-2'-fluoro-5'-isopropyloxyphenyl)-5-hydroxy-3-(trifluoromethyl)pentanamide (1.2 g, 3.2 mmol) in 100 ml methylene chloride, was added thionyl chloride (0.24 ml) in one portion via pipette. The solution turned brown. It was heated to 40°-50° C. for about 7 hours, kept at room temperature for 64 hours, heated to 40° C. for 3 hours, then stirred at room temperature for 18 hours. Then additional thionyl chloride (0.1 ml) was added and heating to 40° C. was resumed for about 4 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dried in vacuo (50° C.) and the resulting golden brown, semi-solid mixture was purified via flash chromatography (20 ml fractions, 2'×7' column, 1:9 ethyl acetate/hexanes) to yield a brown solid, m.p. of 57°-63° C.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=1)[C:11]([CH3:20])([CH3:19])[CH2:10][CH2:9]2.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23]>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:21])[C@@:3]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:30](=[O:31])[C:27]4[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=4)[CH:16]=3)[C:11]([CH3:19])([CH3:20])[CH2:10][CH2:9]2)[N:4]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC1(C)CC[C@@]2(N=C(N)OCC2(F)F)c2cc(N)ccc21
Product: CC1(C)CC[C@@]2(N=C(N)OCC2(F)F)c2cc(NC(=O)c3ccc(C#N)cn3)ccc21
Yield: 65 %

Procedure:
The condensation of (R)-5′,5′-difluoro-4,4-dimethyl-3,4,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-[1,3]oxazine]-2′,7-diamine (intermediate A7.2) and 5-cyanopicolinic acid yielded the title compound (65% yield) as a pale yellow solid. MS (ISP): m/z=426.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:25])[CH2:21][C:22](O)=[O:23])[C:15]2[CH:26]=[CH:27][CH:28]=[CH:29][C:14]=2[C:13]2[CH:30]=[CH:31][CH:32]=[CH:33][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:40])([F:39])[CH2:36][CH2:37][NH2:38]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:25])[CH2:21][C:22]([NH:38][CH2:37][CH2:36][C:35]([F:40])([F:39])[F:34])=[O:23])[C:15]2[CH:26]=[CH:27][CH:28]=[CH:29][C:14]=2[C:13]2[CH:30]=[CH:31][CH:32]=[CH:33][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCCC(F)(F)F
Product: O=C(CC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21)NCCC(F)(F)F

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-malonamic acid and 3,3,3-trifluoropropylamine, the title compound was prepared in the same manner as described for example 1c. Colorless, waxy solid (90%). MS: m/e=540(M+H+).
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>C(#N)C.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: C[C@H](O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 40 h

Procedure:
After (S)-1-phenylethyl alcohol (300 mg, 2.46 mmol), triphenylphosphine (772 mg, 2.95 mmol), 4-nitrobenzoic acid (493 mg, 2.95 mmol), and acetonitrile (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (692 mg, 2.95 mmol) dissolved in acetonitrile (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 40 hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (R)-1-(4-nitrobenzoyloxy)-1-phenylethane as a pale yellow liquid substance (202 mg, yield: 30%/(S)-1-phenylethyl alcohol).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:10][C:11]1[N:12]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([N:23](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[C:14]=2[N:42]=1)[CH3:9].[OH-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:8]([NH:10][C:11]1[N:12]([CH2:43][CH:44]([CH3:45])[CH3:46])[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:23])[C:14]=2[N:42]=1)[CH3:9]
Reactant: CCNc1nc2c(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc3ccccc3c2n1CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNc1nc2c(N)nc3ccccc3c2n1CC(C)C
Temperature: 50 °C
Yield: 19.5 %

Procedure:
Trifluoroacetic acid (20 mL) was added to N2-ethyl-N4,N4-bis(4-methoxybenzyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine (2.0 g, 3.8 mmol), and the reaction was heated at 50° C. for four hours and allowed to cool to ambient temperature. Aqueous sodium hydroxide (6 M) was added to adjust the solution to pH 9, and then dichloromethane and saturated aqueous sodium bicarbonate were added. The organic layer was separated and washed twice with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered through a layer of CELITE filter agent, and concentrated under reduced pressure. The residue was purified twice by automated flash chromatography (silica cartridge, eluting with 12% methanol in dichloromethane followed by silica cartridge, eluting with 3-12% methanol in dichloromethane). The resulting product was recrystallized from acetonitrile containing a few drops of methanol, combined with material from another run, and recrystallized again using the same solvents to provide 210 mg of N2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine as beige needles, mp 188-190° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH-:4].[C:5]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:24][C:23]3[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH3:28])[C:20](=[O:29])[N:19]([CH2:30][CH2:31][CH3:32])[C:18]=3[N:17]=2)=[CH:12][CH:11]=1)([OH:7])=[O:6].O[N:34]1[C:55](=[O:56])[NH:54][C@H:53]2[C@@H:35]1[CH2:36][S:37][C@H:38]2[CH2:39][CH2:40][CH2:41][CH:42](N1C(=O)CCC1=O)[C:43](=[O:45])O.CO.CCOCC>CN(C=O)C>[C:43]([NH:1][CH2:2][CH2:3][NH-:4])(=[O:45])[CH2:42][CH2:41][CH2:40][CH2:39][C@H:38]1[C@@H:53]2[C@@H:35]([NH:34][C:55]([NH:54]2)=[O:56])[CH2:36][S:37]1.[C:5]([CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:24][C:23]3[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH3:28])[C:20](=[O:29])[N:19]([CH2:30][CH2:31][CH3:32])[C:18]=3[N:17]=2)=[CH:14][CH:15]=1)([OH:7])=[O:6]
Reactant: [NH-]CCN
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Agent: CCCn1c(=O)c2[nH]c(-c3ccc(OCC(=O)O)cc3)nc2n(CCC)c1=O
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CO
Product: [NH-]CCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
Compound 6d (24.1 mg, 0.056 mmol) was suspended in 1 ml DMF. N-Hydroxysuccinimido-d-biotin (Sigma, 23.6 mg, 0.069 mmol) was added with stirring. A solution formed after several minutes, and a precipitate appeared soon thereafter. After one day methanol (1 ml) and ether were added. The precipitate was collected and dried (yield 26.6 mg, 73%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH3:26].[OH-].[Na+]>CN(C=O)C.CO>[CH3:26][N:25]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:33][CH:34]=1)[CH3:24]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: COc1cccc(C(Cl)=C2C(=O)N(C(C)=O)c3ccccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccccc32)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(3-methoxyphenyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[Br:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br.[Br-].[Na+]>C(O)C>[Br:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1ccccc1Br
Agent: [Br-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1Br)C(=O)OCC
Yield: 70.8 %

Procedure:
Diethyl malonate (77 g, 0.48 mol) was added to a stirred solution of sodium (10.2 g, 0.425 mol) in ethanol (800 ml) followed by 2-bromobenzyl bromide (100 g, 0.40 mol). Sodium bromide began to separate towards the end of the addition and the mixture became warm. The reaction was completed by refluxing on a steam bath for 3 hours and then cooling overnight. The bulk of the solvent was removed in vacuo, water was added and the product extracted into ether. After drying (CaCl2) and evaporation the product was distilled to give 93.28 g (71%) of material of bp0.2 130° C. (lit bp0.004 115°-120° C., F. G. Holliman and F. G. Mann J. Chem. Soc. 9, [1960]).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5](=O)[C:4]1=[O:14])[CH3:2].O.NN.Cl>CCOC(C)=O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:14])[CH3:2]
Reactant: CCN1C(=O)C(=O)c2cc(C)ccc21
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1C(=O)Cc2cc(C)ccc21
Temperature: 110 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
A mixture of 1-ethyl-5-methyl-1H-indole-2,3-dione (ix-a, 1.53 g, 8.09 mmol) and hydrazine monohydrate (30 mL, 618 mmol) was heated to 110° C. After 5 h, the reaction was cooled to RT and conc. HCl was added to adjust the reaction mixture to approximately pH 3. The mixture was stirred overnight, and poured into a separatory funnel containing EtOAc (150 mL). The mixture was shaken and the layers were separated. The aqueous layer was extracted with EtOAc (2×150 mL) and the combined organic layers were dried, filtered and concentrated to give 1-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one (i-a, 1.03 g, 72.5%). NH4OAc QC conditions. DAD Retention time =1.48 min. M+H=176.