Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:8]([F:19])[C:7]=1[F:20].C([Li])(CC)C.[F:31][C:32]1[C:37]([F:38])=[C:36]([O:39][CH2:40][CH3:41])[CH:35]=[CH:34][C:33]=1[CH:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1.Cl>C(OCC)(=O)C.C1COCC1>[F:20][C:7]1[C:8]([F:19])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]1[CH:21]=[CH:22][C:23]([C:45]2[CH2:46][CH2:47][CH:42]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[C:37]([F:38])[C:32]=3[F:31])[CH2:43][CH:44]=2)=[C:24]([F:25])[C:2]=1[F:1]
Reactant: CCCCCCOc1ccc(CCc2cccc(F)c2F)c(F)c1F
Reactant: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(CCc2ccc(C3=CCC(c4ccc(OCC)c(F)c4F)CC3)c(F)c2F)c(F)c1F
Temperature: 30 °C
Reaction time: 2 h

Procedure:
1-(2,3-Difluorophenethyl)-2,3-difluoro-4-(hexyloxy)benzene (s-24) (3.6 g) and THF (100 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00M; n-hexane and cyclohexane solution; 12 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 1-(2,3-Difluoro-4-ethoxyphenyl)-cyclohexan-4-one (s-25) (2.6 g) in a THF (50 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for 8 hours while the mixture was allowed to return to 25° C. The resulting reaction mixture was poured into a vessel containing a 1N-HCl aqueous solution (100 ml) and ethyl acetate (100 ml) and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous layers, and the extraction was carried out. The resulting organic layers were separated, and washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. p-Toluenesulfonic acid (0.19 g) and toluene (100 ml) were added, and the mixture was heated to reflux for 2 hours, while distilled water was removed. After the reaction solution had been cooled to 30° C., water (200 ml) and toluene (100 ml) were added and mixed with it. The mixture was then allowed to stand until it had separated into two layers of organic and aqueous layers, and the extraction into an organic layer was carried out. The resulting organic layers were separated, and washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent, and further purified by recrystallization from a mixed solvent of Solmix A-11 and heptane (Solmix A-11:heptane=1:2 by volume) and dried to give 1-(2,3-difluoro-4-(hexyloxy)phenethyl)-4-(4-(4-ethoxy-2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorobenzene (No. 487) (3.1 g). The yield based on the compound (s-24) was 33.8%.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:2]=1.[CH3:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][CH2:9][C:10]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]2[CH3:19])=[O:12])[CH:2]=1
Reactant: O=C(O)CCNc1cccc(-c2ccccc2)c1
Reactant: CC1CCCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCCCN1C(=O)CCNc1cccc(-c2ccccc2)c1
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of the 3-(biphenyl-3-ylamino)-propionic acid 1.6 g (6.6 mmol), 2-methylpiperidine 0.78 g (7.9 mmol), was added the solid O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate 4.7 g (1.3 mmol), and triethylamine 3.86 mL (27 mmol) in 25 mL of dichloromethane and left overnight at room temperature. The reaction mixture was washed with water, the organic layer, dried over magnesium sulfate, filtered, and concentrated under vacuum. The compound was purified using silica gel chromatography and was eluted with ethyl acetate, yield to 2 g material.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][CH3:32])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C)C=O>[CH2:31]([C:20]1[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:8][C:34](=[O:35])[O:36][CH2:37][CH3:38])[C:18]=2[N:19]=1)[CH3:32]
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1nc2ccccc2c2c1nc(CC)n2CCCCNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Triethylamine (3.86 mL, 10 eq) was added to a chilled (ice/water bath) suspension of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide (1.0 g, 1 eq) in N,N-dimethylformamide (DMF) (10 mL). Ethyl chloroformate (1.5 g, 5 eq) was added dropwise to give a clear solution. The reaction mixture was allowed to come to ambient temperature with stirring for 2 hours. Additional triethylamine (3.86 mL, 10 eq) and ethyl chloroformate (3.86 mL, 10 eq) were added and the reaction mixture was stirred overnight. The reaction mixture was poured onto crushed ice and then extracted with dichloromethane (50 mL). The organic layer was washed sequentially with water (2×50 mL), 4% sodium carbonate (50 mL), water (50 mL), and brine (50 mL) and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel eluted with a linear gradient of 0-25% CMA in chloroform, 2500 mL) followed by recrystallization from acetonitrile to provide 0.815 g of ethyl 2-ethyl-1-{4-[(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-ylcarbamate as a white crystalline solid, mp 185-187° C. Anal calcd for C20H27N5O4S: C, 55.41; H, 6.28; N, 16.15. Found: C, 55.30; H, 6.29; N, 16.24.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:45])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][CH2:41][CH2:42][O:43][CH3:44])[N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][CH2:41][CH2:42][O:43][CH3:44])[N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:45])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: COCCNc1nc(C)cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Product: COCCNc1nc(C)cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (128 mg, 0.5 mmol) and 3-{3-[2-(2-methoxy-ethylamino)-6-methyl-pyrimidin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K51) (212 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (122 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)([CH2:11][OH:12])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].CCN(CC)CC>ClCCl>[CH3:20][S:21]([O:12][CH2:11][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:9][O:10][S:21]([CH3:20])(=[O:23])=[O:22])(=[O:23])=[O:22]
Reactant: OCC(CO)(c1cccc(Br)c1)c1cccc(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(COS(C)(=O)=O)(c1cccc(Br)c1)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a stirred solution of 2,2-bis(3-bromophenyl)propane-1,3-diol (6.0 g, 15.54 mmol) in dichloromethane (50 mL) at 0° C. was added methanesulfonic chloride (27.1 g, 155 mmol) and Et3N (17.3 mL, 124 mmol) to give an orange solution. The reaction mixture was stirred at 0° C. for 1 h, then at 40° C. for 8 h. The reaction was washed with aq. NH4Cl (80 mL). The aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layers were dried and concentrated. The residue was purified by chromatography (on silica gel column, Petroleum ether: EtOAc=2:1) to afford 3.2 g of the title compound (5.9 mmol, 38%). LC/MS: [M+18]=560. 1HNMR (CDCl3), 400 MHz: δ 2.93 (s, 6H), 4.49 (s, 4H), 7.15-7.48 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].[O:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][CH:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)[CH:3]=1
Reactant: Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (325 mg, 1.0 mmol) in MeOH (10 mL) was added dihydro-2H-pyran-4(3H)-one (88 mg, 1.0 mmol) and AcOH (0.05 mL). The mixture was stirred at 25° C. for 2 h. NaBH3CN (630 mg, 10.0 mmol) was added, and the resulting mixture was stirred at 25° C. for 16 h. The reaction solution was concentrated, and the residue was dissolved in water, extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (200 mg, Yield 48.9%). 1H NMR (CD3OD, 400 MHz): δ 8.44 (brs, 1H), 7.32-7.20 (m, 3H), 7.20-7.13 (m, 2H), 7.13-7.09 (m, 1H), 7.08-7.00 (m, 1H), 6.86-6.77 (m, 1H), 4.39 (s, 2H), 4.35-4.25 (m, 1H), 4.03-3.89 (m, 2H), 3.63-3.40 (m, 7H), 3.31-3.07 (m, 4H), 2.06-1.92 (m, 2H), 1.55-1.40 (m, 2H). LCMS (m/z): 410.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH:9]2[CH2:18][CH2:17][C:12]3([O:16]CCO3)[CH2:11][CH2:10]2)[C:6]([CH3:19])=[CH:5][C:3]=1[NH2:4].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[C:24]([C:34]([F:37])([F:36])[F:35])=[CH:23][N:22]=1.Cl.CO>CC(O)C>[F:1][C:2]1[C:3]([NH:4][C:21]2[N:26]=[C:25]([NH:27][C:28]3[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=3)[C:24]([C:34]([F:35])([F:37])[F:36])=[CH:23][N:22]=2)=[CH:5][C:6]([CH3:19])=[C:7]([CH:9]2[CH2:10][CH2:11][C:12](=[O:16])[CH2:17][CH2:18]2)[CH:8]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2C(F)(F)F)n[nH]1
Reactant: Cc1cc(N)c(F)cc1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3F)ncc2C(F)(F)F)n[nH]1
Temperature: 125 °C

Procedure:
A mixture of 2-fluoro-5-methyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline (318.6 mg, 1.2 mmol), 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine (333.0 mg, 1.2 mmol) and HCl (4 N in water, 0.3 mL, 1.2 mmol) in i-PrOH (4.0 mL) was heated at 125° C. in an oil bath overnight. The reaction mixture was concentrated in vacuo. The resulting crude mixture was dissolved in THF (4 mL), MeOH (2 mL) and HCl (4N in water, 0.3 mL, 1.2 mmol), and stirred at room temperature for an additional 2 h. The reaction mixture was concentrated in vacuo, and purified by silica chromatography (0-100% EtOAC in hexanes gradient) to afford 4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone; ESMS m/z 463.2 (M+H+).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22](=[O:29])(=[O:28])[NH:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:30]>C(O)(=O)C>[Br:1][C:14]1[C:9]([C:8]2[N:4]([CH3:3])[C:5]([CH3:30])=[N:6][CH:7]=2)=[N:10][C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:22](=[O:29])(=[O:28])[NH:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:20][CH:21]=2)=[N:12][CH:13]=1
Reactant: COCCNS(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3C)n2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COCCNS(=O)(=O)c1ccc(Nc2ncc(Br)c(-c3cnc(C)n3C)n2)cc1
Temperature: 60 °C
Yield: 59.1 %

Procedure:
Bromine (8 μl, 0.14 mmol) was added to a solution of 4-(1,2-dimethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine (Example 35; 52 mg, 0.13 mmol) in glacial acetic acid (2 ml) heated at 60° C. The mixture was heated at 60° C. for 4 hours, then the solvent was removed by evaporated. The residue was dissolved in DCM (20 ml), washed with saturated aqueous sodium hydrogen carbonate solution (20 ml), dried (Chemelut column 1005) and purified by flash chromatography eluting with DCM/2% methanolic ammonia (100:0 increasing in polarity to 97:3) to yield the title compound (37 mg, 60%) as a white foam NMR 2.40 (s, 3H), 3.06 (q, 2H), 3.20 (s, 3H), 3.36 (t, 2H), 3.68 (s, 3H), 5.00 (t, 1H), 7.56 (s, 1H), 7.67 (d, 2H), 7.73 (d, 2H), 7.80 (s, 1H), 8.53 (s, 1H); m/z 483.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][N:5]=1.[CH2:15](Br)[CH:16]=[CH2:17]>CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([Cl:3])=[N:5][CH:6]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Oc1cnc(Cl)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1cnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a stirring solution of NaH (0.334 g, 8.35 mmol) in DMF (10 mL) at 0° C. was added 1-chloroisoquinolin-4-ol (1 g, 5.57 mmol). The mixture was stirred at 0° C. for 10 min. before the addition of allyl bromide (0.808 g, 6.68 mmol) dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and then quenched with 1N HCl solution. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to get the crude material. The material was purified by flash chromatography with 20% of EtOAc/hexane to afford 4-(allyloxy)-1-chloroisoquinoline (1.0 g, 4.55 mmol, 83% yield) as a white solid. MS: MS m/z 220.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]([CH3:29])[NH:24][CH2:23][CH2:22]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[C:26](=[CH:27][CH:28]=[C:19]([C:15]5[O:14][CH:18]=[CH:17][CH:16]=5)[CH:20]=4)[CH:25]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(-c3ccco3)ccc21
Product: CC1c2ccc(-c3ccco3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Furan-2-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C([O:8][C:9]([CH:11]([N:18]1[CH2:21][CH:20]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[C:19]1=[O:33])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[C:9]([CH:11]([N:18]1[CH2:21][CH:20]([N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[C:19]1=[O:33])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:10])=[O:8]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)C(c1ccccc1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C(c1ccccc1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Yield: 81 %

Procedure:
1-(α-Benzyloxycarbonylbenzyl)-3-phthalimido-2-azetidinone (1.32 g) was dissolved in ethyl acetate (30 ml), and to the solution, there was added 10% palladium on carbon (500 mg), and the mixture was subjected to catalytic reduction in a stream of hydrogen gas at ordinary temperature and ordinary atmospheric pressure. After a calculated volume of the hydrogen gas was absorbed into the reaction mixture in the course of 3 hours. The reaction mixture was adjusted to about pH 8 with 2% aqueous sodium bicarbonate. The catalyst was removed by filtration from the reaction mixture and the aqueous layer was separated from the resultant filtrate. The aqueous solution was adjusted to pH 2 with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by distillation from solution under reduced pressure to give an crystalline residue, which was washed with diethyl ether to give 1-(α-carboxybenzyl)-3-phthalimido-2-azetidinone (0.85 g), mp 182° to 183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=[O:13].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(OC)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A solution of of 2,5-dimethoxyphenylacetic acid (1.00 g, 5.10 mmol) in 10 mL of acetic acid was added 6.5 mL of 1.0M HNO3 in acetic acid. The reaction was stirred at ambient temperature for 10 min, and diluted with 75 mL of water. The yellow precipitate was collected and washed with water (3×10 mL), then dried on the filter. Recrystallization from 20 mL of 2-propanol gave 846 mg (69%) of the titled compound as fine yellow crystals.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[CH3:9][C:10]([CH3:14])=[CH:11][CH:12]=[O:13]>C1COCC1>[OH:13][CH:12]([CH:11]=[C:10]([CH3:14])[CH3:9])[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: CC(C)=CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)=CC(O)CC#N
Temperature: -78 °C
Reaction time: 2 h
Yield: 108 %

Procedure:
Acetonitrile (11.5 mL, 219 mmol) in THF (300 mL) was cooled to −78° C. and n-BuLi (2.5 M in hexanes, 96 mL) was added slowly. The mixture was stirred at −78° C. for 2 h. 3-Methyl-2-butenal (25 mL, 262 mmol) dissolved in dry THF (50 mL) was added slowly and after 15 min the reaction was quenched with HCl (3N, 175 mL). After evaporation of the majority of solvents, the residue was extracted twice with diethylether. The combined ether extracts were dried (sodium sulfate), filtered and concentrated to give crude 3-hydroxy-5-methyl-hex-4-enenitrile (29.6 g, 100%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:15])=[C:9]([C:11]([NH:13][NH2:14])=[O:12])[N:10]=2)[CH:7]=1.Cl.[N:17]([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:15])=[C:9]([C:11]([N:13]=[N+:14]=[N-:17])=[O:12])[N:10]=2)[CH:7]=1
Reactant: Cc1c(C(=O)NN)nc2ccc(F)cn12
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1c(C(=O)N=[N+]=[N-])nc2ccc(F)cn12
Temperature: 0 °C
Yield: 98.1 %

Procedure:
Compound 6-A (1.8 g, 8.65 mmol) was dissolved in 2N HCl (21.6 mL, 43.2 mmol) and cooled in an ice bath. A solution of NaNO2 (0.716 g, 10.4 mmol) in water (3 mL) was added dropwise over 5 minutes and the resultant solution was stirred on the ice bath for 25 minutes, then made basic with careful addition of a saturated aqueous solution of NaHCO3. A solid precipitate was collected by filtration, then dissolved in CH2Cl2 and dried over Na2SO4. The solvent was evaporated in vacuo to afford compound 6-B as a cream colored solid (1.86 g, 98%). 1H-NMR (CDCl3): δ 7.81-7.87 (m, 1H), 7.64 (dd, J=10.0, 5.2 Hz, 1H), 7.16-7.25 (m, 1H), 2.80 (s, 3H); MS: m/z 220.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:17]([O:14][C:13]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:8]([C:9]([O:11][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:10])[CH:7]=1)=[O:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: CCCCCCCCCCBr
Product: CCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCC)cc([N+](=O)[O-])c1

Procedure:
Using this procedure the reaction of 5-nitroisophthalic acid with 1-bromodecane gave 5-nitro-1,3-benzenedicarboxylic acid didecyl ester (mp 48°-50°, Anal. Calcd for C28H45NO6 : C, 68.40; H, 9.23; N, 2.85. Found: C, 67.68; H, 9.13; N, 2.86.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[N:28]=[CH:29][C:30]([C:33]([OH:35])=O)=[N:31][CH:32]=1.CCN(C(C)C)C(C)C.[F:45][C:46]([F:59])([F:58])[C:47]1[NH:48][C:49]2[C:54]([CH:55]=1)=[CH:53][C:52]([CH2:56][NH2:57])=[CH:51][CH:50]=2>CN(C=O)C>[CH3:25][O:26][C:27]1[N:28]=[CH:29][C:30]([C:33]([NH:57][CH2:56][C:52]2[CH:53]=[C:54]3[C:49](=[CH:50][CH:51]=2)[NH:48][C:47]([C:46]([F:59])([F:45])[F:58])=[CH:55]3)=[O:35])=[N:31][CH:32]=1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: COc1cnc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(C(=O)NCc2ccc3[nH]c(C(F)(F)F)cc3c2)cn1
Reaction time: 24 h
Yield: 60.7 %

Procedure:
To a stirred solution of HATU (121 mg, 0.319 mmol) in DMF (1 ml) was added 5-(methyloxy)-2-pyrazinecarboxylic acid (AniChem LLC; 49.2 mg, 0.319 mmol) in DMF (0.5 ml), followed by DIPEA (0.084 ml, 0.479 mmol) and finally {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 40 mg, 0.160 mmol) in DMF (1 ml). The solution was stirred for 24 hrs. DMF was removed using a rotary evaporator followed by addition of DCM and sodium bicarbonate solution. The mixture was poured through a phase separation cartridge. The organic layer was evaporated to dryness and purified using MDAP to give the title compound as a white solid (34 mg);
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:26]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=[O:33])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccncc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-4-oxo-1-phenyl-3-{[(pyridine-4-carbonyl)-amino]-methyl}-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from intermediate I and isonicotinoyl chloride. MS calcd. for C24H19ClN3O4 [(M+H)+] 448.1, obsd. 447.9.
Reaction SMILES: [F:1][C:2]([F:23])([C:19]([F:22])([F:21])[F:20])[CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:14]([O:16]CC)=O)[N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12.[NH3:24]>>[F:1][C:2]([F:23])([C:19]([F:21])([F:22])[F:20])[CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:14]([NH2:24])=[O:16])[N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12
Reactant: N
Reactant: CCOC(=O)c1nc(CCC(F)(F)C(F)(F)F)c2ncccn12
Product: NC(=O)c1nc(CCC(F)(F)C(F)(F)F)c2ncccn12

Procedure:
A solution of the intermediate from Step D (0.3684 g, 1.092 mmol) and ammonia (11.70 mL, 82 mmol, 7 N in MeOH) was heated at 50° C. under N2 in a screw cap vial for 24 h. The reaction mixture was concentrated in vacuo to remove the excess amine to afford the desired product, as a yellow solid. m/z=309.1 (M+H).