Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:10]=[N:9][C:8]=1[C:19]([N:21]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25][C@H:24]([C:35]([O:37]C)=[O:36])[CH2:23]1)=[O:20].[OH-].[Na+]>CO>[C:31]([O:30][C:28]([N:26]1[CH2:27][C@@H:22]([N:21]([C:19]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[O:20])[CH2:39][CH:40]([CH3:41])[CH3:42])[CH2:23][C@@H:24]([C:35]([OH:37])=[O:36])[CH2:25]1)=[O:29])([CH3:32])([CH3:34])[CH3:33]
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a solution of 1-tert-butyl 3-methyl (3R,5S)-5-[{[5-(4-methoxybutyl)-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (1.47 g) in methanol (10 ml) was added 4N aqueous sodium hydroxide solution (5 ml), and the mixture was stirred at 50° C. for 30 min. The solvent was concentrated under reduced pressure, and the residue was neutralized with 10% aqueous citric acid solution, extracted with ethyl acetate (30 ml×2) and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (1.3 g) as an amorphous compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].[N:14]1[NH:15][C:16](=[O:20])[CH:17]=CC=1>>[O:20]=[C:16]1[NH:15][N:14]=[C:1]([C:4]2[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:2]=[CH:17]1
Reactant: CC(=O)c1cccc(CC(=O)O)c1
Reactant: O=c1cccn[nH]1
Product: O=C(O)Cc1cccc(-c2ccc(=O)[nH]n2)c1

Procedure:
5 g of 3-acetylphenylacetic acid (preparation described in Can. J. Chem.; 82; 12; 2004; 1760-1768) are converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=O>C(OCC)(=O)C>[C:5]([NH:7][CH:13]([NH:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[CH:8]=1)[C:12]([O:16][CH3:17])=[O:15])(=[O:6])[CH3:4]
Reactant: COC(=O)C=O
Reactant: NC(=O)c1cc(Cl)cc(Cl)c1
Solvent: CCOC(C)=O
Product: COC(=O)C(NC(C)=O)NC(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 8 h
Yield: 15.4 %

Procedure:
A mixture of 3,5-dichlorobenzamide (19.0 g) and methyl glyoxylate (8.8 g) in ethyl acetate (300 ml) was heated under reflux for 8 hours. The solvent was removed and the residual adduct was crystallised from chloroform-light petroleum. A portion (4.0 g) of the adduct was dissolved in a mixture of glacial acetic acid (30 ml) and acetonitrile (10 ml) with stirring, and then concentrated sulphuric acid (4 ml) was added. The mixture was kept at room temperature overnight when water (100 ml) was added. The precipitated solid was washed with water, dried, and crystallised from ethanol to give the product (2.45 g) as a colourless crystalline solid, m.p. 235°-237°.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([CH3:42])=[C:6]([NH:10][C:11]([C:13]2[C:21]3[N:20]=[C:19]([NH:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[NH:18][C:17]=3[CH:16]=[C:15]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:41])([F:40])[F:39])=[O:31])[CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1.[CH3:43]I>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[C:5]([CH3:42])=[C:6]([NH:10][C:11]([C:13]2[C:21]3[N:20]=[C:19]([NH:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[N:18]([CH3:43])[C:17]=3[CH:16]=[C:15]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:39])([F:40])[F:41])=[O:31])[CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(NCC(C)(C)CO)nc12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2c1nc(NCC(C)(C)CO)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide powder (6.2 mg) was added to a solution of N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (80 mg) in DMF (2 mL), the solution was stirred at room temperature for 30 minutes, methyl iodide (8.7 μL) was added, and it was stirred for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with brine, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (20 mg) as white powder. This was suspended in MeOH, 2N hydrogen chloride/EtOH (1 Eq) was added, it was stirred to obtain a solution, and the solvent was removed under reduced pressure. The residue was washed with diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (15 mg) as white powder.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][CH2:14][CH:13]([N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=2[CH:32]=1)C>C(O)C.[OH-].[Na+]>[CH2:25]([N:17]([CH:13]1[CH2:12][C:11]2[CH:32]=[C:7]([O:6][CH2:5][C:4]([OH:33])=[O:3])[CH:8]=[CH:9][C:10]=2[CH2:16][CH2:15][CH2:14]1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)COc1ccc2c(c1)CC(N(Cc1ccccc1)C(=O)OC(C)(C)C)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2ccc(OCC(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 2-[8-(N-benzyl-N-tert-butoxycarbonyl-amino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (1.6 g) in ethanol (16 ml) was added aqueous iN sodium hydroxide at 5° C., and the mixture was stirred at room temperature for 1 hour. After evaporation in vacuo, the residue was dissolved into a mixture of aqueous 0.1N hydrochloric acid and ethyl acetate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was triturated with hexane and dried in vacuo to give 2-[8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid (1.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([Br:14])[CH:7]=1)[CH3:2].IC.[CH3:18][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([Br:14])[CH:7]=1)[CH3:18])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)Cc1ccc(OC)c(Br)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1ccc(OC)c(Br)c1
Temperature: -78 °C

Procedure:
To (3-bromo-4-methoxy-phenyl)-acetic acid ethyl ester (12.2 mmol) in THF was added iodomethane (0.75 mL, 12.2 mmol), and the mixture was cooled to −78° C. Sodium bis(trimethylsilyl)amide (1M in THF; 12.2 mL, 12.2 mmol) was added, and subsequent work-up gave the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[NH:4][C:3]1=[O:14].[CH2:15]1[C@H:24]2[C@H:19]([CH2:20][CH2:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)[NH:18][CH2:17][CH2:16]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:15]1[C@H:24]2[C@H:19]([CH2:20][CH2:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)[N:18]([C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:14])[NH:4][C:5]=3[CH:10]=2)=[O:13])[CH2:17][CH2:16]1
Reactant: Cn1c(=O)[nH]c2cc(C(=O)O)ccc21
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1c(=O)[nH]c2cc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)ccc21
Yield: 15 %

Procedure:
The title compound is prepared from 1-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 15% of theory; LC (method 4): tR=1.92 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:43](O)/[CH:44]=[CH:45]/[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl>[C:46]1([CH:45]=[CH:44][CH2:43][O:2][C:1](=[O:3])[CH2:4][N:5]2[CH2:27][CH2:26][CH2:25][C@H:6]2[C:7]([N:9]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: OC/C=C/c1ccccc1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)OCC=Cc1ccccc1
Yield: 38.3 %

Procedure:
Using the procedure described previously, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (65 mg, 0.17 mmol), 4-N,N-dimethylaminopyridine (12.5 mg, 0.10 mmol, 0.6 eq), 1,3-dicyclohexylcarbodiimide (64 mg, 0.31 mmol, 1.8 eq) in dichloromethane (5.0 mL) was treated with trans cinnamyl alcohol (29 uL, 0.22 mmol, 1.3 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 32 mg (38%) of L-isoleucine, N-[1-(2-(3-phenyl-2-propen-1-oxy)-2 -oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[OH:20].C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CC(C)=O>[CH2:29]([O:20][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[N:10]=[CH:9][N:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:28]=[CH2:27]
Reactant: COc1cc2ncnc(Nc3ccccc3)c2cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc2c(Nc3ccccc3)ncnc2cc1OC
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 7-methoxy-4-phenylamino-quinazolin-6-ol (0.56 g, 2.1 mmol) (from Example 15, Step B, supra) in acetone (50 mL) was added K2CO3 (1.45 g, 10 mmol), and allyl bromide (0.2 mL, 2.3 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:4:0.04) as eluent to give the desired (6-allyloxy-7-methoxy-quinazolin-4-yl)-phenyl-amine as a yellow solid. (Yield 0.6 g, 93%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[C:2]=[O:3].[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[NH:1]([C:2]([NH:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:29])[CH3:30])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1)=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C=Nc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)Nc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using isocyanatobenzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 422.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[C:24]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:23]=[CH:22][N:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[CH:25]=[C:24]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:23]=[CH:22][N:21]=1)=[O:19]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C(=O)CBr)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cc(CO[Si](C)(C)C(C)(C)C)ccn2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromoacetyl-4-[(tert-butyldimethylsilyloxy)methyl]pyridine (step 4).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Na].Br[CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=[O:14]>>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C@H:12]([C:13]([OH:15])=[O:14])[CH:16]([CH3:18])[CH3:17]
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC(C)C(Br)C(=O)O
Agent: [Na]
Product: CC(C)[C@H](Nc1ccc(Cl)cc1F)C(=O)O

Procedure:
Following the procedure of Example 6, 2-fluoro-4-chloroaniline is reacted with m-phenoxy-α-cyanobenzyl α-bromoisovalerate to give the m-phenoxy-α-cyanobenzyl ester of N-(2-fluoro-4-chlorophenyl)valine, MS m/e 452 (M+). Alternatively 2-fluoro-4-chloroaniline is reacted with the sodium salt of α-bromoisovaleric acid to give N-(2-fluoro-4-chlorophenyl)valine, which is then esterified using m-phenoxy-α-cyanobenzyl bromide or mesylate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([CH3:11])=[CH:4][CH:3]=1.[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:8]([C:7]1[C:6]([CH3:10])=[C:5]([CH3:11])[CH:4]=[CH:3][C:2]=1[NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:22])#[N:9]
Reactant: Cc1ccc(N)c(C#N)c1C
Reactant: O=C=NC(=O)c1ccccc1
Product: Cc1ccc(NC(=O)NC(=O)c2ccccc2)c(C#N)c1C

Procedure:
Prepared as in Example 53a from 6-amino-2,3-dimethylbenzonitrile and benzoyl isocyanate as a off-white solid (210 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 3H), 2.43 (s, 3H), 7.48 (d, J=6.4 Hz, 2H), 7.53 (t, J=8 Hz, 7.6 Hz, 2H), 7.65 (t, J=7.2 Hz, 1H), 7.94 (d, J=8 Hz, 1H), 8.03 (d, J=7.6 Hz, 2H), 11.29 (s, 1H), 11.37 (s, 1H). MS 293 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=3)[CH:19]=[CH:20][C:21]=2OS(C(F)(F)F)(=O)=O)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[CH2:43]([Sn](CCCC)(CCCC)CCCC)[CH:44]=C.O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=3)[CH:19]=[CH:20][C:21]=2[CH:43]=[CH2:44])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc(N(CC)CC)c(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 103.2 %

Procedure:
g of ethyl 3″-tert-butyl-4″-diethylamino-4′-trifluoromethanesulfonyloxy[1,1′;3′,1″]terphenyl-4-carboxylate (2 mmol) are dissolved at room temperature in 23 mL of dimethylformamide, and 250 mg of LiCl (6 mmol) and 0.74 mL of allyltributyltin (2.4 mmol) are then added. The reaction medium is heated and, at 40° C., 70 mg of dichlorobis(triphenylphosphine)palladium (0.1 mmol) are added and the reaction medium brought to 120° C. and stirred for 20 minutes. The reaction is stopped by adding 30 mL of water and then extracted with 30 mL of ethyl acetate. The organic phases are washed with 80 mL of water and then dried over magnesium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on silica gel (eluent: heptane). 940 mg of ethyl 3″-tert-butyl-4″-diethylamino-4′-vinyl[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=100%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH2:9]P(OCC)(=O)OCC)[O:6][N:5]=1.COC([O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O)C>CS(C)=O>[CH3:3][C:4]1[CH:8]=[C:7]([CH:9]=[CH:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[OH:22])[O:6][N:5]=1
Reactant: CCOP(=O)(Cc1cc(C)no1)OCC
Reactant: COC(C)Oc1ccccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C=Cc2ccccc2O)on1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8.8 g (0.2 mole) of a 55% strength suspension of sodium hydride in paraffin oil are introduced into 100 ml of absolute dimethylsulfoxide. 47 g (0.2 mole) of diethyl (3-methyl-isoxazol-5-yl)-methanephosphonate are added dropwise at room temperature. The mixture is then stirred for 30 minutes, after which 36 g (0.2 mole) of o-(1-methoxyethoxy)-benzaldehyde are added dropwise, with continued stirring. The reaction mixture is then stirred for 24 hours at room temperature and is poured onto 1 liter of ice water, and the batch is extracted 3 times with 80 ml of methylene chloride at a time. The combined organic phases are dried with sodium sulfate and evaporated down on a rotary evaporator. The oily residue is dissolved in 80 ml of methanol and 10 ml of water, 2 ml of 5 N HCl are added, and the mixture is stirred for 10 minutes. Excess water is then added slowly until a precipitate forms. This is filtered off, washed with water and recrystallized from ethanol. 19 g (47% of theory) of colorless crystals, of melting point 236°-238° C., are obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].S(OC)(O[CH3:21])(=O)=O>O>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C:11](=[O:13])[N:10]([CH3:21])[C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(c2cccc(I)c2)C(=O)N1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN1C(=O)CN(c2cccc(I)c2)C1=O
Reaction time: 4 h

Procedure:
1-(3-Iodophenyl)imidazolidine-2,4-dione (0.588 g) was suspended in water (13 ml) and treated with potassium hydroxide (0.37 g). The reaction was placed in a warming bath (45° C.) and treated with dimethyl sulfate (0.784 ml). After stirring for 4 h the reaction mixture was chilled and filtered. The cake was washed with water and dried to give the title compound (0.381 g). LCMS RT=2.94 min.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]2[CH2:11][O:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)#[N:21]>CC#N>[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][CH2:11][C@@H:9]([OH:10])[C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:24][CH:23]=1)#[N:21]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H]1CO1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CNCc1ccc(C#N)cc1
Yield: 57.8 %

Procedure:
To a solution of tert-butyl (S)-2-cyclohexyl-1-((S)-oxiran-2-yl)ethylcarbamate (67.3 mg, 0.25 mmol) in CH3CN (8 mL) was added 4-cyanobenzylamine (39.6 mg, 0.3 mmol) and the mixture was heated under reflux overnight. The solvent was removed in vacuo and the residue was purified by the preparative HPLC to give tert-butyl (2S,3R)-4-(4-cyanobenzylamino)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (58 mg, 58%). 1H NMR: 0.82 (m, 1H), 0.95 (m, 1H), 1.10-1.48 (m, 5H), 1.45 (s, 9H), 1.55-1.68 (m, 5H), 1.76 (m, 1H), 2.65 (m, 2H), 3.46 (m, 1H), 3.85 (m, 2H), 4.49 (m, 1H), 7.42 (d, 2H), 7.59 (d, 2H). MS (E/Z): 402 (M+H+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[C:10]([Br:12])[CH:11]=1.[N:13]1[O:14][CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][C:17]=12.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1>[Br:12][C:10]1[CH:11]=[C:7]([C@@:17]23[CH2:18][O:19][CH2:20][CH2:21][C@H:16]2[CH2:15][O:14][NH:13]3)[S:8][CH:9]=1
Reactant: C1CC2CON=C2CO1
Reactant: Brc1csc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Brc1csc([C@@]23COCC[C@H]2CON3)c1
Reaction time: 1 h

Procedure:
n-Butyllithium (2.63 M, 2.99 ml) was added dropwise to a solution of 2,4-dibromothiophene (2.00 g) in toluene-THF (10:1) (22 ml) at −78° C. After stirring at the same temperature for one hour, a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (500 mg) in toluene-THF (10:1) (10 ml) and a boron trifluoride-diethyl ether complex (990 μl) were added dropwise at the same time. After stirring at the same temperature for two hours, an ammonium chloride solution was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (700 mg).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]3([C:20]([O:22][CH3:23])=[O:21])[CH2:19][CH:18]=[CH:17][CH2:16]3)[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Cl>CO.[Pt](=O)=O>[F:24][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:14][C@@H:13]([C:15]3([C:20]([O:22][CH3:23])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:12][CH2:11][NH:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)C1(c2ccnc(-c3ccc(C(F)(F)F)cc3)c2)CC=CC1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1([C@H]2CCN[C@@H](c3ccc(C(F)(F)F)cc3)C2)CCCC1
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A mixture of the pyridine from Step 1 (270 mg, 0.77 mmol) platinum (IV) oxide (30 mg) and HCl solution (4N in dioxan, 0.2 ml, 0.8 mmol) in MeOH (15 ml) was hydrogenated at 20 psi on a Parr® apparatus for 0.5 hours. The catalyst was removed by filtration and the filtrate evaporated in vacuo. The residue was purified by chromatography on silica, eluting with 1-2% 2M NH3 in MeOH/DCM to give the title compound (168 mg, 61%) as an oil The give the desired piperidine as white solid (7.1 g, quant). M/Z (ES+) 348 (MH+). The product was contaminated with a small amount of over reduced material: M/Z (ES+) 362 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8]([N:17]3[CH2:18][CH2:19][CH2:20][N:14]([CH3:13])[CH2:15][CH2:16]3)=[N:7][C:6]=2[CH:11]=1
Reactant: CN1CCCNCC1
Reactant: Cc1cc(Cl)cc2nc(S)oc12
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc2nc(N3CCCN(C)CC3)oc12

Procedure:
5-Chloro-7-methyl-2-mercaptobenzoxazole (200 mg) was dissolved in toluene (10 ml), N-methylhomopiperazine (1.24 ml) was added dropwise to the solution and then the mixture was stirred with heating for 1 hour. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 5-chloro-7-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (266 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17](=[O:18])[CH:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[NH4+].[Cl-].[N-:27]=[N+]=[N-].[Na+]>CO>[NH2:27][C:16]1[C:17](=[O:18])[C:10]2[O:9][C:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=3)=[C:12]([CH3:13])[C:11]=2[C:14](=[O:22])[C:15]=1[CH2:19][CH2:20][CH3:21]
Reactant: CCCC1=CC(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCC1=C(N)C(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O

Procedure:
To a solution of 2-(4-methoxybenzyl)-3-methyl-5-propyl-4,7-benzofurandione (from Example 28) (295 mg, 0.91 mmol) in MeOH (3 mL) were added NH4Cl (109 mg) and NaN3 (130 mg). The mixture was heated to reflux for 4 hours and the solvent was then removed in vacuo. Water was added and the product was extracted into CH2Cl2 and chromatographed on silica gel (15% EtOAc/hexane) to give the title compound.