Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8].CN1CCOCC1.[C:20]1(=[O:45])[N:24]([NH:25][C@H:26]([C:37](O)=[O:38])[CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)[C:23](=[O:40])[C:22]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:21]12.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(Cl)Cl>[C:23]1(=[O:40])[N:24]([NH:25][C@H:26]([C:37]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][OH:2])=[O:38])[CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)[C:20](=[O:45])[C:21]2=[CH:44][CH:43]=[CH:42][CH:41]=[C:22]12
Reactant: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)[C@@H](N)CCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](CCCCO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The above crude 6-hydroxy-L-norleucine, methyl ester, hydrochloride was dissolved in dimethylformamide (6 ml.) and methylene chloride (25 ml.) and treated with 4-methylmorpholine (1.30 ml., 1.20 g., 11.8 mmol.). The solution was cooled to 0° C. and treated with N-phthalimido-L-tryptophan followed by hydroxybenzotriazole (925 mg., 6.8 mmol.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.438 g., 7.5 mmol.). The mixture was stirred at 0° C. for 0.5 hour and then at room temperature for 2.5 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed successively with 0.5N hydrochloric acid, water, 5% sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give 3.06 g., of title product as a yellow foam. TLC: (ethyl acetate) Rf =0.35.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([NH2:8])[CH:7]=1.[F:17][C:18]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:19]=1[C:20]([NH:22][C:23]1[C:24]([C:28](O)=[O:29])=[N:25][NH:26][CH:27]=1)=[O:21].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([NH:8][C:28]([C:24]2[C:23]([NH:22][C:20](=[O:21])[C:19]3[C:18]([F:17])=[CH:34][CH:33]=[CH:32][C:31]=3[F:35])=[CH:27][NH:26][N:25]=2)=[O:29])[CH:7]=1
Reactant: CN1CCC(Oc2ccc(F)cc2N)CC1
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCC(Oc2ccc(F)cc2NC(=O)c2n[nH]cc2NC(=O)c2c(F)cccc2F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-fluoro-2-(1-methyl-piperidin-4-yloxy)-phenylamine) (0.049 g, 0.22 mmol) was combined with 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (0.053 g, 0.20 mmol), EDC (0.048 g, 0.25 mmol), HOBt (0.034 g, 0.25 mmol) and DMF (1 ml) and the resulting reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was reduced in vacuo and purified by preparative LC/MS to give 4-(2,6-Difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid [5-fluoro-2-(1-methyl-piperidin-4-yloxy)-phenyl]-amide as a buff solid. (0.010 g, 11%) (LC/MS: Rt 2.19, [M+H]#474.27).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH2:5][NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: Cc1cc(C)cc(C=O)c1
Product: Cc1cc(C)cc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3,5-Dimethylbenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:20][N:21]([CH3:30])[C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[S:18][CH:19]=3)=[CH:11][CH:10]=2)[S:3]1>O1CCOCC1.[Pd]>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[C:17]([CH2:20][N:21]([CH3:30])[C:22](=[O:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[S:18][CH:19]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CN(Cc1cc(-c2ccc(C=C3SC(=O)NC3=O)cc2)cs1)C(=O)c1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CN(Cc1cc(-c2ccc(CC3SC(=O)NC3=O)cc2)cs1)C(=O)c1ccccc1
Reaction time: 6 h
Yield: 74.7 %

Procedure:
2 g (1 mass equivalent) of palladium-on-charcoal are added to a solution of 2 g (4.6 mmol) of N-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenyl]thiophen-2-ylmethyl}-N-methylbenzamide in 20 ml of dioxane that has been degassed beforehand, and the reaction medium is placed under 3 atm of hydrogen, at 50° C. for 6 hours. After filtering off the palladium through Celite, the filtrate is concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 9.5/0.5 dichloromethane/methanol mixture. 1.5 g (75%) of N-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenyl]thiophen-2-ylmethyl}N-methylbenzamide are obtained in the form of a solid with a melting point of 134° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1>>[C:9]1([C:6]2[N:5]=[CH:4][C:3]([CH2:2][C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)=[CH:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1cnc(-c2ccccc2)nc1
Reactant: OB(O)c1cccnc1
Product: c1ccc(-c2ncc(Cc3cccnc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 64a (100 mg, 0.41 mmol) and pyridine-3-boronic acid (74 mg, 0.60 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:2) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. Light orange solid. Yield: 72 mg, 71%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.76 (s, 2H), 7.00-7.05 (m, 1H), 7.23-7.29 (m, 4H), 8.16-8.22 (m, 2H), 8.27-8.36 (m, 2H), 8.40-8.43 (m, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=33.5, 123.7, 128.0, 128.6, 130.5, 130.7, 134.2, 136.1, 137.2, 148.4, 150.0, 157.3, 163.3; (ESI): m/z=247.92 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:30])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[C:3]=1[O:31][CH3:32].[OH-].[Na+].[CH2:35](O)C>>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH2:30][CH3:35])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[C:3]=1[O:31][CH3:32]
Reactant: CCO
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Br)c1OC)C(C)(C)CC=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC/C(=C(F)/C=C/C(C)=C/C(=O)O)c1cc2c(c(Br)c1OC)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure J-1, ethyl (2E,4E,6E)-7-(4-bromo-8-isopropyl-3-methoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoate (Compound A-157, 43 mg, 0.085 mmol) in ethanol was treated with a solution of 1 N NaOH to produce the title compound after purification by recrystallization from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)([O-:26])=[O:25].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(Cc2ccc([N+](=O)[O-])cc2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
110 mg (0.37 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of DMF. 17 mg (0.44 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 76 mg (0.44 mmol) of 4-nitrobenzyl chloride was added to the obtained mixture and they were stirred at 60° C. overnight. The reaction mixture was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]12[C:17]2=[CH:18][C:19]3[O:23][CH2:22][O:21][C:20]=3[CH:24]=[C:16]2[O:15][CH2:14]1.Br[CH2:26][C:27]1[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:26][C:27]1[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1)[C:8](=[O:13])[C:7]12[C:17]2=[CH:18][C:19]3[O:23][CH2:22][O:21][C:20]=3[CH:24]=[C:16]2[O:15][CH2:14]1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCO4)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCO4)C(=O)N2Cc1ccc(C(F)(F)F)o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
To a suspension of sodium hydride (0.03 g, 0.63 mmol, 60% dispersion in mineral oil) in N,N-dimethylformamide (5.00 mL) was slowly added a solution of 5′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.10 g, 0.33 mmol) in N,N-dimethylformamide (5.00 mL) at 0° C. After stirring for 15 minutes at 0° C., a solution of 2-(bromomethyl)-5-(trifluoromethyl)furan (0.11 g, 0.49 mmol) in N,N-dimethylformamide (40.0 mL) was added. The resulting mixture was stirred at ambient temperature for 4 h and quenched with water (20.0 mL). The mixture was extracted with ethyl acetate (3×25.0 mL). The combined organic layers was washed with water (50.0 mL) and brine (2×25.0 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography eluting with ethyl acetate/hexane (15-50%) to afford the title compound (0.11 g, 77% yield): mp 96-98° C.; 1H NMR (300 MHz, CDCl3) δ 7.09 (d, 1H), 7.00 (s, 1H), 6.87 (d, 1H), 6.74 (d, 1H), 6.52 (s, 1H), 6.38 (d, 1H), 6.11 (s, 1H), 5.88 (d, 2H), 4.96 (ABq, 2H), 4.80 (ABq, 2H), 2.29 (s, 3H); MS (ES+) m/z 444.2 (M+1).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C:6]([F:9])([F:8])[F:7])(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH:23]1[C:28]([OH:29])=[CH:27][CH:26]=[C:25]([Br:30])[CH:24]=1>CN(C=O)C>[Br:30][C:25]1[CH:26]=[CH:27][C:28]([O:29][CH2:5][C:6]([F:9])([F:8])[F:7])=[CH:23][CH:24]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Br)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 54 %

Procedure:
To a stirred solution of trifluoroethyl tosylate (1.5 g, 5.8 mmol) in DMF (20 mL) was added K2CO3 (4 g, 29.4 mmol) followed by p-bromo phenol (1.1 g, 6.46 mmol) at RT under an inert atmosphere. The reaction mixture was stirred at 120° C. for 6 h. The volatiles were evaporated under reduced pressure; the residue was diluted with water (5 mL) and extracted with EtOAc (3×30 mL). The organic layer was washed with water and brine, was dried over anhydrous Na2SO4, was filtered and was concentrated in vacuo. The crude compound was purified by silica gel column chromatography eluting with 5% EtOAc/hexane to afford the desired product (0.8 g, 3.13 mmol, 53.3%) as semi solid. 1H NMR (200 MHz, CDCl3): δ 7.44-7.38 (m, 2H), 6.86-6.80 (m, 2H), 4.38-4.25 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[C:23](Cl)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:20])[F:21])[CH:13]=2)=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:25])[CH3:24]
Reactant: Nc1nccc(C(=O)NCc2cccc(OC(F)(F)F)c2)n1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1nccc(C(=O)NCc2cccc(OC(F)(F)F)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(3-(trifluoromethoxy)benzyl)pyrimidine-4-carboxamide (15 mg, 0.05 mmol, Step-1) and acetyl chloride (11 mg, 0.14 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([SH:19])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:26]([O:30][C:31](=[O:39])[CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)([CH3:29])([CH3:28])[CH3:27]>CC(C)=O>[C:26]([O:30][C:31](=[O:39])[CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][S:19][C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:11]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: Sc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)COCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COCCCCSc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Yield: 82.2 %

Procedure:
To a solution of 500 mg of 5,6-diphenyl-2-pyrazinethiol in 20 ml of acetone, 321 mg of sodium carbonate was added and a solution of 556 mg of 2-(4-bromobutyloxy)acetic acid tert-butyl ester in 2 ml of acetone was added dropwise while stirring under ice-cooling, followed by stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and then the residue was combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 701 mg of the desired compound as a pale yellow oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH2:15])([O-:3])=[O:2].N1C=CC=CC=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:15][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O-:3])=[O:2]
Reactant: Nc1cc(N2CCCC2)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(N2CCCC2)ccc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-nitro-5-(pyrrolidin-1-yl)benzenamine (4 mmol) and pyridine (8 mmol) in dry dichloromethane (15 mL) was added dropwise benzoyl chloride (8 mmol). The reaction mixture was stirred at room temperature for 8 h. The solvent was evaporated in vacuum, and the residue was subjected to flash chromatography on silica gel using a mixture of hexanes and CH2Cl2 as eluent to afford N-(2-nitro-5-(pyrrolidin-1-yl)phenyl)benzamide as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:30][CH2:29][CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: NCC1CCOCC1
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1

Procedure:
The method described in Part E of Example 1 can be used to treat 7-benzyloxy-4-chloro-3-nitroquinoline with tetrahydro-2H-pyran-4-ylmethylamine to provide (7-benzyloxy-3-nitroquinolin-4-yl)(tetrahydro-2H-pyran-4-ylmethyl)amine. The same method can be used to treat 6-benzyloxy-4-chloro-3-nitroquinoline with tetrahydro-2H-pyran-4-ylmethylamine to provide (6-benzyloxy-3-nitroquinolin-4-yl)(tetrahydro-2H-pyran-4-ylmethyl)amine.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:19][C:20](=[O:33])[CH:21]=[CH:22][C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.Cl.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([NH:1][CH2:2][C@@H:3]([NH:19][C:20](=[O:33])/[CH:21]=[CH:22]/[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)(=[O:44])[CH3:43]
Reactant: COc1ccc(C#N)cc1C=CC(=O)N[C@H](CN)CN1CCC(Oc2ccc(F)cc2)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CNC(C)=O)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of E)-N-{(R)-1-aminomethyl-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-3-(5-cyano-2-methoxy-phenyl)-acrylamide.HCl salt (0.35 g, 0.66 mmol) and triethylamine (0.27 ml, 1.99 mmol) in DCM (5 ml) is treated with acetyl chloride (0.042 ml, 0.6 mmol) at 5° C. The reaction mixture is stirred at ambient temperature for 1 hour then washed with water, saturated aqueous NaHCO3 and brine. The organic phase is dried over MgSO4 and the solvent evaporated. The crude product is purified by flash chromatography (elution methanol:DCM; 4:96) to afford (E)-N-{(R)-1-(acetylamino-methyl)-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-3-(5-cyano-2-methoxy-phenyl)-acrylamide. [MH]+ 495.0.
Reaction SMILES: S(Cl)(Cl)=O.O[C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[NH:11][C:12]1[N:13]([CH3:29])[C:14](=[O:28])[C:15]2[C:16](=[N:18][NH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]=1>C(Cl)Cl>[CH3:29][N:13]1[C:14](=[O:28])[C:15]2=[C:20]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][N:18]=[C:16]2[N:17]2[C@H:6]3[CH2:10][CH2:9][CH2:8][C@H:7]3[N:11]=[C:12]12
Reactant: Cn1c(N[C@@H]2CCC[C@H]2O)nc2n[nH]c(Nc3ccccc3)c2c1=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN1C(=O)c2c(n[nH]c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
2.0 M solution of thionyl chloride in CH2Cl2 (7.5 mL, 15.4 mmol) is added dropwise to a solution of 6-((1R,2R)-2-hydroxycyclopentylamino)-5-methyl-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (3.5 g, 10.3 mmol) in CH2Cl2 (30 mL) at room temperature. After the completion of the addition, the reaction mixture is stirred at r.t. for 2 h. Solvent and excess SOCl2 are removed under reduced pressure. The residue is suspended in water (100 mL), and then carefully neutralized with 7% ammonium hydroxide (5 mL) to pH=6.5-7. The mixture is extracted with CH2Cl2 and MeOH (10:1, v/v) five times. The combined organic phase is washed with water, dried over Na2SO4, and then evaporated under reduced vacuum to give 2.9 g of crude product. MS (ESI) m/z 323.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:28]2[CH:33]=[C:32]([C:34]3[O:39]C(C)(C)[O:37][C:36](=O)[CH:35]=3)[CH:31]=[CH:30][N:29]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:36](=[O:37])[CH2:35][C:34]([C:32]1[CH:31]=[CH:30][N:29]=[C:28]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:33]=1)=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2ccnc(-n3ccnc3)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1ccnc(-n2ccnc2)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 6-(2-imidazol-1-yl-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J14) according to the general procedure K. Obtained as a brown solid (361 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([OH:32])[CH:30]([CH3:31])[CH2:29][CH2:28][CH:27]2[CH:23]1[CH2:24][NH:25][CH2:26]2>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([OH:32])[CH:30]([CH3:31])[CH2:29][CH2:28][CH:27]2[CH:23]1[CH2:24][N:25]([C:11](=[O:13])[CH2:10][C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=1)[CH2:26]2
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: COc1ccccc1C1(O)C(C)CCC2CNCC21
Product: COc1ccccc1C1(O)C(C)CCC2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Yield: 39.5 %

Procedure:
By working according to the experimental procedure of Example 16, from 1.21 g of 3-indoleacetic acid and 1.39 g of (3aRS,4RS,5RS,7aSR)-4-(2 -methoxyphenyl)-5-methyl-4-perhydroisoindolol, and after purification on a column of silica gel (particle size 0.04-0.06 mm, diameter 2.8 cm, height 25 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (40/60 by volume), 0.88 g of (3aRS,4RS,5RS,7aSR)-4-(2-methoxyphenyl)-2-(3-indolylacetyl)-5-methyl-4-perhydroisoindolol is obtained in the form of a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][Br:31])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCO)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
4-Methoxyphenethyl alcohol (50 g) and triphenylphosphine (103 g) were dissolved in methylene chloride (600 ml), followed by the addition of N-bromosuccinimide (70 g) in small portions under ice-cooling, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated, and to the resulting residue was added hexane. The insoluble matters were filtered off, while the resulting filtrate was evaporated, to give the title compound as a colorless oil (50.32 g, yield; 71%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[CH2:24]([C:26]([C:48]1[CH:53]=[CH:52][C:51]([B:54]2[O:58][C:57]([CH3:60])([CH3:59])[C:56]([CH3:62])([CH3:61])[O:55]2)=[C:50]([CH3:63])[CH:49]=1)([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]2([O:42][Si](C)(C)C)[CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:31]([CH3:47])[CH:30]=1)[CH2:27][CH3:28])[CH3:25]>>[CH2:24]([C:26]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]2([OH:42])[CH2:38][CH2:39][CH2:40][CH2:41]2)=[C:31]([CH3:47])[CH:30]=1)([C:48]1[CH:53]=[CH:52][C:51]([B:54]2[O:58][C:57]([CH3:59])([CH3:60])[C:56]([CH3:61])([CH3:62])[O:55]2)=[C:50]([CH3:63])[CH:49]=1)[CH2:27][CH3:28])[CH3:25]
Reactant: CCC(CC)(c1ccc(CCC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(CCC2(O)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 3 h
Yield: 51 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.33 mL, 1.33 mmol) was added to 2-[4-(1-ethyl-1-{3-methyl-4-[2-(1-trimethylsilanyloxy-cyclopentyl)-ethyl]-phenyl}-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 34-(1); 0.25 g, 0.48 mmol), and the mixture was stirred for three hours. The reaction mixture was purified by silica gel chromatography (14% ethyl acetate/hexane) to give the title compound (0.12 g, 53%).