Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:14]=1)[O:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9]1.C(OC([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][C@@H:25]1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C>>[CH2:30]([C@@H:25]1[NH:24][CH2:29][CH2:28][N:27]([C:2]2[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([O:7][C@H:8]3[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9]3)[CH:14]=2)[CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Reactant: COc1ccc(Br)cc1O[C@H]1CCN(C)C1
Product: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1O[C@H]1CCN(C)C1

Procedure:
The title compound was prepared by the method outlined for Example 1 using (3S)-3-(5-Bromo-2-methoxyphenoxy)-1-methylpyrrolidine as the aryl halide and 2(S)-benzyl-piperazine-1-carboxylic acid tert-butyl ester as the amine component. The title compound was isolated as an orange oil. 1H NMR (MeOH-d4) 7.33-7.30 (m, 2H), 7.26-7.22 (m, 3H), 6.83 (d, J=9.2, 1H), 6.44 (m, 2H), 4.81 (m, 1H), 3.73 (s, 3H), 3.36-3.28 (m, 2H), 3.04 (m, 2H), 2.93-2.66 (m, 8H), 2.52-2.46 (m, 1H), 2.36 (s, 3H), 2.19 (m, 1H), 1.95 (m, 1H).
Reaction SMILES: O[C@:2]1([C:12]([OH:14])=[O:13])[CH2:6][CH2:5][C:4]([CH2:8][OH:9])([CH3:7])[C:3]1([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:7][C:4]12[C:3]([CH3:11])([CH3:10])[C@@:2]([C:12]([OH:14])=[O:13])([CH2:6][CH2:5]1)[O:9][CH2:8]2
Reactant: CC1(CO)CC[C@](O)(C(=O)O)C1(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC12CC[C@@](C(=O)O)(OC1)C2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 222A (125 mg) and triphenylphosphine (366 mg) in tetrahydrofuran (10 mL) at 0° C. was added dropwise diisopropylazodicarboxylate (0.27 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was partitioned between 1 N aqueous NaOH (10 mL) and ether (20 mL) and the layers separated. The aqueous phase was extracted twice with ether to remove non-polar organic extracts, then acidified with 1 N aqueous HCl and extracted with ether (3×). The organic extracts were dried (MgSO4), filtered and solvent evaporated to afford the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 0.93 (s, 3H), 0.95 (s, 3H), 1.04 (s, 3H), 1.5-1.6 (m, 1H), 1.73-1.85 (m, 1H), 1.88-1.97 (m, 1H), 2.24-2.35 (m, 1H), 3.60 (d, 1H), 3.76 (dd, 1H).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:38]=2)O1>>[N:41]1([CH2:40][CH2:39][N:37]2[CH:38]=[C:34]([C:25]3[CH:2]=[CH:3][C:4]4[O:13][CH2:12][CH2:11][C:10]5[S:9][C:8]([C:14]6[N:15]([CH2:19][C:20]([F:21])([F:22])[F:23])[N:16]=[CH:17][N:18]=6)=[N:7][C:6]=5[C:5]=4[CH:24]=3)[CH:35]=[N:36]2)[CH2:42][CH2:43][O:44][CH2:45][CH2:46]1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cnn(CCN4CCOCC4)c3)cc1-2
Yield: 17 %

Procedure:
8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine were reacted under palladium Suzuki conditions to give 115 (17% yield). LC/MS (ESI+): m/z 532 (M+H). 1H NMR (400 MHz, DMSO) δ 8.48 (d, J=2.1, 0H), 8.30 (s, 0H), 8.07 (s, 0H), 7.76 (s, 0H), 7.49 (dd, J=8.3, 2.2, 0H), 7.09 (d, J=8.3, 0H), 5.89 (q, J=8.6, 0H), 4.38 (t, J=4.9, 0H), 4.25 (t, J=6.6, 0H), 3.61-3.51 (m, 1H), 3.48 (t, J=4.9, 0H), 2.75 (t, J=6.6, 0H), 2.45-2.35 (m, 1H)
Reaction SMILES: [N:1](=[C:3]([C:7](=[O:9])[CH3:8])[C:4](=O)[CH3:5])O.[NH2:10][CH:11](C(O)=O)[CH2:12][CH2:13][CH3:14]>C(O)CCC>[C:7]([C:3]1[NH:1][C:11]([CH2:12][CH2:13][CH3:14])=[N:10][C:4]=1[CH3:5])(=[O:9])[CH3:8]
Reactant: CCCC(N)C(=O)O
Reactant: CC(=O)C(=NO)C(C)=O
Solvent: CCCCO
Product: CCCc1nc(C)c(C(C)=O)[nH]1
Yield: 48.5 %

Procedure:
To 40 g (0.309 moles) of 3-oximino-2,4-pentanedione dissolved in 200 ml of n-butanol was added 39.92 g (0.341 moles) of d,1-norvaline. The resulting mixture was brought to reflux, while stirring rapidly under nitrogen with an oil bath. After 19.3 h the reaction mixture was cooled, and then suction filtered. The residue was washed with ethyl acetate (100 ml) and the combined filtrates concentrated in vacuo. The resulting oil was dissolved in ethyl acetate (200 ml) and extracted with three 50 ml portions of 5% aqueous sodium hydroxide solution. Removal of the solvent in vacuo gave 0.15 moles (55.7% yield based on recovered d,1-norvaline) of 5-acetyl-4-methyl-2-propylimidazole.
Reaction SMILES: [CH2:1]([C@@H:7]([C@@H:18]([O:39][Si](C(C)(C)C)(C)C)[CH2:19][C@H:20]([O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([C@@H:7]([C@@H:18]([OH:39])[CH2:19][C@H:20]([O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCC[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CCCCCC)C(=O)OCc1ccccc1)OC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCC[C@H](C[C@H](O)[C@H](CCCCCC)C(=O)OCc1ccccc1)OC1CCCCO1
Reaction time: 12 h
Yield: 60.4 %

Procedure:
(g) 480 mg of benzyl (2S,3S,5R)-2-hexyl-3-[(t-butyldimethylsilyl)oxy]-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate and 350 mg of tetrabutylammonium fluoride trihydrate were dissolved in 8 ml of THF and stirred for 12 hours. After evaporation the residue was dissolved in 50 ml of ether and washed with water. The ethereal phase was dried and evaporated. The product was chromatographed on silica gel. There were obtained 240 mg of benzyl (2S,3S,5R)-2-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate, MS: 463 [(M+H)+ -dihydro-2H-pyran-2-yl].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)(O)=[O:11]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: O=C(O)c1ccncc1
Reactant: COc1ccccc1N
Product: COc1ccccc1NC(=O)c1ccncc1
Yield: 97.3 %

Procedure:
Using o-anisidine (2.34 g, 19.0 mmol) and 4-carboxypyridine (2.29 g, 19.0 mmol), the procedure of Reference Example 11 was repeated to obtain 4.22 g (97.2%) of the title compound in the form of colorless powder.
Reaction SMILES: Cl[C:2]1[N:14]=[CH:13][N:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][C:7]3[N:17]([CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[N:16]=[CH:15][C:8]=3[C:9]=1[S:10]2.Cl.[O:28]1[CH2:33][CH2:32]OCC1>C(O)(C)C>[CH3:4][C:5]1[CH:6]=[C:7]([NH:17][C:2]2[C:3]3[C:4]4[CH2:5][CH2:6][C:7]5[N:17]([CH2:18][CH2:19][N:20]6[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]6)[N:16]=[CH:15][C:8]=5[C:9]=4[S:10][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:8]=[CH:32][C:33]=1[OH:28]
Reactant: C1COCCO1
Reactant: CN1CCN(CCn2ncc3c2CCc2c-3sc3ncnc(Cl)c23)CC1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2ncnc3sc4c(c23)CCc2c-4cnn2CCN2CCN(C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 6-chloro-3-[2-(4-methyl-piperazin-1-yl)-ethyl]-4,5-dihydro-3H-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluorene (150 mg, 0.39 mmol) and 4-amino-O-cresol (71 mg, 0.58 mmol) in isopropanol (5 mL) was added 4M HCl in dioxane (0.67 mL, 2.7 mmol). The reaction mixture was sealed in a microwave reaction vessel and it was placed in a microwave instrument at 160° C. for 10 min. After it was cooled to room temperature, solvents were evaporated and the residue was dissolved in MeOH/water/DMF and purified by prep. HPLC. After drying, the TFA salt was neutralized with saturated NaHCO3 and extracted with a mixture of CHCl3:isopropanol (v/v, 3:1). The organic phase was dried over Na2SO4 and concentrated to dryness. The desired product was obtained as a pale solid (174 mg, 95%). 1H-NMR (CD2Cl2-d2) δ 8.34 (s, 1H), 7.55 (s, 1H), 7.28 (m, 2H), 6.88 (b, 1H), 6.80 (m, 1H), 4.20 (t, 2H, J=6.2 Hz), 3.38 (t, 2H, J=8.3 Hz), 3.13 (t, 2H, J=8.4 Hz), 2.85 (t, 2H, J=6.2 Hz), 2.62-2.45 (b, 8H), 2.30 (s, 3H), 2.26 (s, 3H); LCMS RT=1.89 min; [M+H]+=476.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH:11]2[OH:26])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[CH2:28][C:29]1[CH:30]=[CH:31][C:32]2[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=2[CH:44]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:12][CH:11]2[O:26][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1F
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC)c(F)c3)cc21

Procedure:
Analogously to Method D, 0.050 g of benzyl 4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate and 0.042 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a colourless resin. Rf=0.26 (2:1 EtOAc-heptane); Rt=5.10.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][NH:7][CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:9]1=2.[CH2:35]=[C:36]1[O:40][C:38](=[O:39])[CH2:37]1>CN(C)C1C=CN=CC=1.O1CCCC1>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[CH2:6][N:7]([C:38](=[O:39])[CH2:37][C:36](=[O:40])[CH3:35])[CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:9]1=2
Reactant: C=C1CC(=O)O1
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc21
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
To a solution of isopropyl 5-(3,5-bistrifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 46, Step 1) (200 mg, 0.39 mmol) and 4-dimethylaminopyridine (6 mg, 0.049 mmol) in dry tetrahydrofuran (1.4 mL) at 0° C. under a nitrogen atmosphere, add a solution of diketene (0.033 mL, 0.43 mmol) in dry tetrahydrofuran (0.4 mL). After stirring 1.5 h at 0° C., remove the solvent under reduced pressure. Purify the by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (169 mg, 73%). MS (ES+): 593 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:16].[H-].[Na+].Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([O:28][CH3:29])[N:21]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([O:28][CH3:29])[N:21]=2)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:4][C:3]=1[CH3:16]
Reactant: COc1nc(Cl)ccc1C#N
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(N(C(=O)OC(C)(C)C)c2ccc(Br)c(C)c2)ccc1C#N
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
To a solution of tert-butyl 4-bromo-3-methylphenylcarbamate (4.36 g, 15.24 mmol) in N,N-dimethylformamide (60 mL) on an ice bath under a nitrogen balloon was added sodium hydride (0.610 g, 15.24 mmol). The reaction was stirred on an ice-water bath for 10 min. The ice bath was removed and to the solution was added a solution of 6-chloro-2-methoxynicotinonitrile (3.85 g, 22.86 mmol) in N,N-dimethylformamide (40 mL) dropwise. After addition completed, the mixture was stirred overnight at 50° C. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the crude product. The crude was then purified by silica gel column (100% hexanes to 8:2 hexanes/ethyl acetate) to give tert-butyl 4-bromo-3-methylphenyl(5-cyano-6-methoxypyridin-2-yl)carbamate (3.15 g, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (s, 9H), 2.30 (s, 3H), 3.55 (s, 3H), 7.00 (dd, J=2.6, 8.4 Hz, 1H), 7.22 (d, J=2.5 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 8.30 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][N:6]([C:8]2[C:12]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][N:10]([CH3:21])[N:9]=2)[C:5](=[O:22])[C:4]1([CH3:24])[CH3:23])=O.[CH3:25][NH:26][CH3:27].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1.C(O)(=O)C>[CH3:25][N:26]([CH2:1][CH:3]1[CH2:7][N:6]([C:8]2[C:12]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[CH:11][N:10]([CH3:21])[N:9]=2)[C:5](=[O:22])[C:4]1([CH3:23])[CH3:24])[CH3:27]
Reactant: CNC
Reactant: Cn1cc(NC(=O)OC(C)(C)C)c(N2CC(C=O)C(C)(C)C2=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)CC1CN(c2nn(C)cc2NC(=O)OC(C)(C)C)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (3-(4-formyl-3,3-dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamate (173 mg) obtained in Step D of Example 4, 2M dimethylamine THF solution (0.39 mL) and acetic acid (30 μL) in THF (5.0 mL) was added sodium triacetoxyborohydride (220 mg). The reaction mixture was stirred at room temperature for 16 hr, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and then HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), and the obtained fraction was concentrated under reduced pressure to give the title compound (112 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:27][C:28](Cl)=[O:29])[CH2:23][CH2:24][CH2:25][CH3:26]>C1C=CC=CC=1>[C:28](=[O:29])([O:27][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCOC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.976 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 0.90 g. of chloroformic acid n-pentyl ester as in Example 1. The 1.5 g. of yellow, partially crystallized oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 90 g. of silica gel. Benzene elutes 1.479 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-pentyl carbonate obtained melts at 50.1°-51.0° and has a clearing point of 61.1°. UV (EtOH): ε270 = 26,800.
Reaction SMILES: [NH2-:1].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>>[NH2:1][C:9]1[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)c1ccncc1
Reactant: [NH2-]
Agent: [Na+]
Product: CC(C)(C)c1ccnc(N)c1
Temperature: 150 °C
Reaction time: 6 h
Yield: 55.2 %

Procedure:
To 790 mg of sodium amide were added 20 mL of N,N-dimethylanaline and 2.74 g of 4-t-butyl pyridine at r.t. The mixture was stirred at 150° C. for 6 hours. During this period, 3 more portions of sodium amide (790 mg each) were added. The reaction was cooled down to r.t. The mixture was partitioned between EtOAc and water. Aqueous layer was extracted with EtOAc (3×). The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography with 50% EtOAc in hexanes followed by 100% EtOAc to give 1.68 g of the title compound as a solid: 1H NMR (500 MHz, CDCl3) δ1.21 (s, 9H), 4.55 (br, 2H) 6.44 (t, J=1.1 Hz, 1H), 6.62 (dd, J=5.5, 1.8 Hz, 1H), 7.94 (d, J=5.5Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[S:16][CH:15]=2)[N:11]([CH3:29])[N:10]=1.[Cl:30]N1C(=O)CCC1=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[S:16][C:15]=2[Cl:30])[N:11]([CH3:29])[N:10]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1csc(-c2cccc(C(F)(F)F)c2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1cc(-c2cccc(C(F)(F)F)c2)sc1Cl
Temperature: 25 °C
Yield: 78.3 %

Procedure:
A solution of 3-(2-chloro-6-fluorophenyl)-1-methyl-5-[5-(3-trifluoromethylphenyl)thien-3-yl]-1H-1,2,4-triazole (0.45 g, 1 mmol) and N-chlorosuccinimide (0.15 g, 1.1 mmol) in methylene chloride/glacial acetic acid (1:1, 2 mL) was refluxed under nitrogen for 2 days, cooled to room temperature, poured into water (10 mL) and extracted with ether (3×20 mL). The combined ethereal extracts were washed with water (3×30 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (30 mL), dried over magnesium sulphate and chromatographed on silica to afford the product as a white solid (0.37 g, 76%): mp 53-54° C.; 1H NMR (CDCl3) δ 7.79 (s, 1H), 7.71 (d, 2H), 7.60 (d, 1H), 7.54 (t, 1H), 7.44 (s, 1H), 7.30-7.40 (m, 2H), 7.11 (t, 1H), 4.05 (s, 3H); EI/MS 472 m/e (M+); Calcd. for C20H11Cl2F4N3S: C, 50.9; H, 2.35; N, 8.90; Found: C, 50.9; H, 2.49; N, 8.82.
Reaction SMILES: CN(C=O)C.[ClH:6].Cl.[NH2:8][CH2:9][C:10]1[O:14][C:13]([C:15]([O:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28](=[NH:30])[NH2:29])[CH:24]=3)[CH:19]=2)=[O:16])=[CH:12][CH:11]=1.[C:31](O)(=[O:36])[CH2:32][C:33]([OH:35])=[O:34].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:6].[C:33]([CH2:32][C:31]([NH:8][CH2:9][C:10]1[O:14][C:13]([C:15]([O:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28](=[NH:29])[NH2:30])[CH:24]=3)[CH:19]=2)=[O:16])=[CH:12][CH:11]=1)=[O:36])([OH:35])=[O:34]
Reactant: O=C(O)CC(=O)O
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)o3)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)CC(=O)O)o3)ccc2c1
Yield: 57.5 %

Procedure:
To a mixture of 210 ml of DMF and 90 ml of pyridine were added 10 g of 6-amidino-2-naphthyl 5-aminomethylfuran-2-carboxylate dihydrochloride, 13.6 g of malonic acid and 320 mg of DMAP, then 10.8 g of DCC was added to the mixture with stirring and ice-cooling, and the mixture was stirred for 24 hours. The precipitate was removed by filtration and the filtrate was added dropwise to 3 l of acetone. The precipitate was collected by filtration to obtain 6.5 g of the intended product as a white solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])([OH:3])=[O:2].O.[C:14]1(C)C=CC(S(O)(=O)=O)=C[CH:15]=1>C(O)C>[C:1]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])([O:3][CH2:14][CH3:15])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCCC1CCCC1=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCC1CCCC1=O

Procedure:
In the manner described in Example 3, treatment of 2-(3-carboxypropyl)cyclopentan-1-one (Example 5) with p-toluene sulfonic acid monohydrate in ethanol gives a colorless oil, b.p. 93°C. (0.10 mm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1>CO.C(OCC)(=O)C.[OH-].[Pd+2].[OH-].[C]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(-c3cccc(F)c3)n[nH]c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(-c3cccc(F)c3)n[nH]c2c1
Reaction time: 7.5 h
Yield: 53.6 %

Procedure:
To a solution of 300 mg of 3-(3-fluorophenyl)-6-nitro-1H-indazole in 5 ml methanol and 2.5 ml ethyl acetate was added 60 mg of 20% palladium hydroxide-carbon (water content: 50%), and the mixture was subjected to hydrogenation at room temperature at normal pressure for 7.5 hours. After adding 2.5 ml of ethyl acetate to the reaction mixture, the catalyst was filtered off through Celite. The solvent was evaporated, and the crude product was suspended in ethyl acetate-diisopropyl ether, to give 142 mg of the title compound as white crystals.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-].[H-].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:17]([C:22](=O)[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O.C(O)(=O)C>CN(C)C=O>[Cl:29][C:25]1[CH:24]=[C:23]([C:22]2[C:17]3[C:14](=[CH:13][C:12]([O:11][CH3:10])=[C:19]([O:20][CH3:21])[CH:18]=3)[CH:15]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:1]=2)[CH:28]=[CH:27][N:26]=1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: COc1cc(C=O)c(C(=O)c2ccnc(Cl)c2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl isocyanoacetate (18 ml) in dimethylformamide (85 ml) is added sodium hydride (7.85 g, 62.4% in oil) with ice-cooling under nitrogen atmosphere, and the mixture is stirred at room temperature for 30 minutes. To a solution of 3,4-dimethoxy-6-(2-chloroisonicotinoyl)benzaldehyde (52.0 g) in dimethylformamide (170 ml) is added dropwise the above solution at 40-50° C., and then the mixture is stirred at 50° C. for one hour. The mixture is neutralized with 10% acetic acid, concentrated, and extracted with chloroform. The extract is washed, and the insoluble materials are collected by filtration, and the filtrate is dried and concentrated. The resultant and the collected insoluble materials are combined, and recrystallized from ether-methanol to give 2-chloro-4-(3-methoxycarbonyl-6,7-dimethoxyisoquinolin-1-yl)pyridine (16.1 g).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=3)[CH:20]=2)[C@@H:13]([CH3:32])[CH2:12]1)=O)C1C=CC=CC=1.[NH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1>>[CH3:32][C@@H:13]1[C@H:14]([NH:17][CH2:18][C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:33][CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=4)[N:26]=3)[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:16][NH:11][CH2:12]1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1NCc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: C[C@H]1CNCC[C@H]1NCc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 136 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G3. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.63 (s, 1H) 8.36 (d, 2H) 7.95 (d, 1H) 7.75 (t, 1H) 7.67 (d, 1H) 7.15 (d, 2H) 6.71 (d, 2H) 4.50 (s, 2H) 3.96 (m, 1H) 3.80 (m, 1H) 3.72 (m, 1H) 3.56 (d, 1H) 3.34 (d, 1H) 3.20 (t, 2H) 2.96 (t, 2H) 2.80 (m, 1H) 2.38 (dd, 2H) 1.36 (d, 3H).