Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:32])=[N:23][C:22]=1[CH3:33])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([N:26]2[CH2:31][CH2:30][CH2:29][CH:28]([CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:27]2=[O:32])=[N:23][C:22]=1[CH3:33])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: O=CCCc1ccccc1
Product: Cc1nc(N2CCCC(CCCc3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 10 %

Procedure:
Following the procedure as described in Example 3, making variations as required to use 3-phenylpropanal in place of cyclopropanecarbaldehyde to react with N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 10% yield: mp 140-141° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.37-7.10 (m, 10H), 5.98 (t, J=4.7 Hz, 1H), 4.55 (d, J=5.3 Hz, 2H), 4.31-4.19 (m, 1H), 4.04-3.91 (m, 1H), 2.69-2.47 (m, 6H), 2.11-1.78 (m, 4H), 1.76-1.53 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 172.8, 162.7, 157.0, 152.2, 142.0, 137.9, 128.8, 128.4, 128.3, 127.9, 127.6, 125.9, 119.2, 47.9, 44.1, 42.2, 35.9, 31.4, 28.9, 25.5, 21.3, 17.4; MS (ES+) m/z 448.21 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH:24]([C:26]1[C:34]2[C:30](=[CH:31][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:33]=2)[CH:29]=[C:28]([O:43][CH3:44])[CH:27]=1)[CH3:25].[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:21][O:22][CH:24]([C:26]3[C:34]4[C:30](=[CH:31][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[N:33]=4)[CH:29]=[C:28]([O:43][CH3:44])[CH:27]=3)[CH3:25])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COc1cc(C(C)Br)c2nn(COCC[Si](C)(C)C)cc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2nn(COCC[Si](C)(C)C)cc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (193 mg, 0.66 mmol) and 7-(1-bromoethyl)-5-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (240 mg, 0.623 mmol) in dimethylformamide (2.5 mL) at 0° C. was added sodium hydride (60% in mineral oil, 32.4 mg, 0.81 mmol). The resulting solution was stirred at 0° C. for 30 min. The reaction was quenched by the cautious addition of saturated ammonium chloride and diluted with diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (15%→25% EtOAc/Hex) gave 29 mg (7.6%) as oil. 1H-NMR (CDCl3, 300 MHz) δ 7.88 (s, 1H), 7.25-7.30 (m, 2H), 6.95-7.00 (m, 2H), 6.6606.71 (m, 2H), 5.60 (s, 2H), 4.88 (q, J=6.0 Hz, 1H), 3.77 (s, 3H), 3.66-3.71 (m, 2H), 3.53-3.59 (m, 2H), 3.28-3.41 (m, 2H), 1.40 (m, 12H), 0.85-0.9 (m, 2H), -0.08 (s, 9H), 13C-NMR (CDCl3, 76 MHz) δ 161.2 (d, J=972 Hz), 155.5, 154.9, 143.9, 138.8, 135.3, 128.8, 122.3, 121.5, 116.1, 115.0, 114.7, 94.9, 81.4, 79.2, 73.9, 67.0, 60.3, 55.1, 41.2, 31.8, 28.4, 22.6, 20.9, 17.7, 14.1, −1.6; Mass spec.: 614.63 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][N+:10]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+].CCOC(C)=O>C1COCC1.CO.[Zn]>[NH2:10][CH2:9][CH:8]([C:7]1[C:2]([CH3:1])=[C:3]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:4]=[CH:5][CH:6]=1)[C:13]1[C:21]2[C:16](=[CH:17][C:18]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:19][CH:20]=2)[NH:15][CH:14]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2cc(N3CCOCC3)ccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(N3CCOCC3)ccc12
Yield: 84.6 %

Procedure:
A heterogeneous solution of benzyl 2-methyl-3-(1-(6-morpholino-1H-indol-3-yl)-2-nitroethyl)phenylcarbamate (1.8743 g, 3.64 mmol), ammonium chloride (2.92 g, 54.6 mmol) and zinc (3.57 g, 54.6 mmol) in THF (Ratio: 1.000, Volume: 79 ml) and methanol (Ratio: 1.000, Volume: 79 ml) was stirred under nitrogen for 2.5 hr. EtOAc (60 mL) was added, and the solution was filtered through a pad of CELITE®. The filtrate was concentrated in vacuo; the residue was dissolved in water (50 mL) and EtOAc (75 mL). After separation of the layers, the aqueous layer was extracted with EtOAc (2×75 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo to give the desired product (1.4934 g, 3.08 mmol, 85% yield) as a tan solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH3:27][C@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([CH3:34])[N:29]1[C:35]([O:37][CH2:38]Cl)=[O:36].C(OCC)(=O)C>CS(C)=O.[Cl-].[Na+].O>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:38][O:37][C:35]([N:29]3[C@H:30]([CH3:34])[CH2:31][CH2:32][CH2:33][C@@H:28]3[CH3:27])=[O:36])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: C[C@@H]1CCC[C@H](C)N1C(=O)OCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H]1CCC[C@H](C)N1C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.7 %

Procedure:
Sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate (300 mg) was added to 5 ml of a solution of 183 mg of (cis-2,6-dimethylpiperidin-1-yl)carbonyloxymethyl chloride in DMSO, and the mixture was stirred at room temperature for 18 hr. Ethyl acetate (20 ml) and 20 ml of 20% brine were added thereto, followed by separation. The organic layer was washed twice with 20% brine, was dried over anhydrous magnesium sulfate, and was filtered, and ethyl acetate was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=15:1) to give 273 mg of the title compound.
Reaction SMILES: [H][H].C([O:10][C:11]1[CH:24]=[C:23]([O:25]CC2C=CC=CC=2)[C:22]([C:33]([N:35]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([OH:44])[CH:41]=3)[CH2:36]2)=[O:34])=[CH:21][C:12]=1[C:13]([N:15]([CH2:17][CH2:18][CH2:19][CH3:20])[CH3:16])=[O:14])C1C=CC=CC=1>[Pd].C1COCC1>[CH2:17]([N:15]([CH3:16])[C:13](=[O:14])[C:12]1[CH:21]=[C:22]([C:33]([N:35]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([OH:44])[CH:41]=3)[CH2:36]2)=[O:34])[C:23]([OH:25])=[CH:24][C:11]=1[OH:10])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN(C)C(=O)c1cc(C(=O)N2Cc3ccc(O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)c1cc(C(=O)N2Cc3ccc(O)cc3C2)c(O)cc1O
Temperature: 22 °C
Reaction time: 20 h
Yield: 55.1 %

Procedure:
10 ml of THF, 200 mg of 5% Pd/C (50.5% of H2O) and 15.884 ml (0.708 mmol) of hydrogen are added to 200 mg (0.354 mmol) of 2,4-bisbenzyloxy-N-butyl-5-(5-hydroxy-1,3-dihydroisoindole-2-carbonyl)-N-methylbenzamide in an autoclave, and the mixture is stirred for 20 h at 22° C. Filtration, subsequent evaporation and chromatography of the residue gives 75 mg (55.1%) of N-butyl-2,4-dihydroxy-5-(5-hydroxy-1,3-dihydroisoindole-2-carbonyl)-N-methylbenzamide “A1”);
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[I:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[N:12]=[C:11]2[C:23](N(OC)C)=[O:24]>C1COCC1>[I:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[N:12]=[C:11]2[CH:23]=[O:24]
Reactant: CON(C)C(=O)c1nn(C2CCCCO2)c2ccc(I)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nn(C2CCCCO2)c2ccc(I)cc12
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Lithium aluminum hydride (160 mg, 4.21 mmol) was added in portions to a cooled (0° C.) solution of 5-iodo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (XI) (1.46 g, 3.5 mmol) in THF. Stirring was continued at 0° C. until the reaction was completed, approximately 30 min. The reaction was quenched by the slow addition of EtOAc at 0° C., and the whole mixture was poured into 0.4 N NaHSO4. The organic layer was washed with brine, dried over MgSO4, concentrated, and purified on a silica gel column (100% EtOAc→3:97 MeOH:DCM) to give 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (I) as a white solid (0.90 g, 3.15 mmol, 72% yield). 1H NMR (DMSO-d6) δ ppm 1.50-1.71 (m, 2H), 1.71-1.87 (m, 1H), 1.97-2.15 (m, 2H), 2.31-2.42 (m, 1H), 3.66-3.99 (m, 2H), 5.96-6.17 (m, 1H), 7.78 (d, J=6 Hz, 1H), 7.84 (d, J=6 Hz, 1H), 8.50 (s, 1H), 10.13 (s, 1H); ESIMS found for C13H13IN2O2 m/z 357 (M+H).
Reaction SMILES: [NH:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][CH2:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]2[CH:46]=[C:45]([O:47][CH3:48])[C:44]([O:49][CH3:50])=[C:43]([O:51][CH3:52])[CH:42]=2)[CH:36]=1>>[ClH:33].[ClH:33].[ClH:33].[C:2]1([N:1]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=4)[CH:16]=3)[CH2:10][CH2:9]2)[CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]3[CH:46]=[C:45]([O:47][CH3:48])[C:44]([O:49][CH3:50])=[C:43]([O:51][CH3:52])[CH:42]=3)[CH:36]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccccc4)CC3)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(N(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)c4ccccc4)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-Anilino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (1.64 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (1.64 g) were reacted in the same manner as described in Preparation Example 9. The title compound was obtained after converting the product to a trihydrochloride.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:18])[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)[CH:4]([CH3:6])[CH3:5].Cl.[CH3:20]I>>[O:18]=[C:14]([CH:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:8][CH:9]=1)[CH3:20])[C:15]([OH:17])=[O:16]
Reactant: CC(C)Cc1ccc(CC(=O)C(=O)O)cc1
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Cc1ccc(C(C)C(=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
A 3N aqueous solution of sodium hydroxide (20 ml; 60 mmoles) was slowly added to a solution of 6.60 g (30 mmoles) of p-isobutylphenylpyruvic acid and 10 ml of methyl iodide. After the addition, the mixture was stirred at room temperature for 4 hours, acidified with 1N hydrochloric acid, and extracted with 150 ml of ether. The ether layer was dried over magnesium sulfate, and the ether was evaporated under reduced pres-sure to give pale yellowish white crystals. The NMR spectrum of the crystals led to the determination that the crystals were nearly pure 2-oxo-3-(p-isobutylphenyl)butanoic acid (4.67 g; yield 67 %).
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][Cl:15].[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>ClCCl>[Cl:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][Cl:15])[S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: ClCCNCCCl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N(CCCl)CCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
8.6 ml (62 mmol) of triethylamine are added to a solution of 5 g (28 mmol) of bis(2-chloroethyl)amine hydrochloride in 60 ml of dichloromethane. After filtration of the salts, 2.4 ml (31 mmol) of methanesulphonyl chloride are added to the filtrate obtained and the reaction medium is stirred at ambient temperature for 3 h. After addition of water, the product is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated. 5.8 g (94%) of N,N-bis(2-chloroethyl)methanesulphonamide are obtained in the form of a beige solid.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][C:19]2([CH3:25])[CH3:24])[CH2:10][CH:9]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][CH3:34])[CH:28]=1)=[O:7].C=O.[C:46](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[Cl:65]CCl>C(O)(=O)C>[ClH:65].[ClH:65].[ClH:65].[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][C:19]2([CH3:24])[CH3:25])[CH2:10][CH:9]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH3:46])[CH3:34])[CH:28]=1)=[O:7]
Reactant: CNc1cccc(CC2CN(CC#CCN3CCOCC3(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: ClCCl
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)c1cccc(CC2CN(CC#CCN3CCOCC3(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-[3-(N-methylamino)benzyl]piperazine (0.19 g), 37% aqueous formaldehyde (50 μl), sodium triacetoxyborohydride (79 mg) and acetic acid (22 μl) in dichloromethane (5 ml) was stirred for 2 hours at room temperature. Then additional 37% aqueous formaldehyde (25 μl), acetic acid (10 μl) and sodium triacetoxyborohydride (40 mg) were added to the reaction mixture and the whole was stirred for further 1 hour. The mixture was poured into aqueous saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (40:1). The fractions containing the objective compound were collected and evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate solution to give 1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-(N,N-dimethylamino)benzyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine trihydrochloride (0.21 g).
Reaction SMILES: [C:1](#N)[CH3:2].Br[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1.C=C>Cl[Pd]Cl.O>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH:1]=[CH2:2])[CH:14]=[CH:13]2
Reactant: CC#N
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: Cl[Pd]Cl
Agent: C=C
Solvent: O
Product: C=Cc1ccc2cc(OC)ccc2c1
Temperature: 60 °C

Procedure:
A 20-gallon jacketed stainless steel reactor equipped with a mechanical agitator is charged with 12.8 kg of ACN, 12.45 kg of DEK and 12.4 kg of 2-bromo-6-methoxynaphthalene (BMN) formed as described in Example 7 hereof, 4.6 g of PdCl2, and 50.9 g of NMDP. The reactor is pressured and vented three times with 50 psig nitrogen. The reactor is then charged with 6.27 kg of TEA. The agitator is set at 158 rpm and the reactor is pressured and vented with 50 psig nitrogen. The agitator is set to 416 rpm, the reactor is pressured to 100 psig with ethylene and heated with tempered water on the jacket. The reaction temperature ranges from 87° to 98° C., while the pressure varies from 394 to 458 psig. The total reaction time is 3.5 hours with a BMN conversion of 99.6% in two hours. The reactor is cooled, vented, and the reactor contents at 60° C. are transferred for workup, to a 30-gallon glass lined reactor equipped with a 6-inch column. The 20-gallon reactor is then charged with 12.5 kg of DEK, which is then heated to 60° C. and transferred to the 30-gallon reactor.
Reaction SMILES: [NH2:1][C:2]1[CH:29]([CH3:30])[CH:6]2[CH2:7][C:8]([CH2:11][C:12]3[CH2:13][CH2:14][N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:28]=[CH:27][N:26]=[CH:25]5)=[CH:20][CH:19]=4)[CH2:16][CH:17]=3)([CH3:10])[O:9][C:5]2=[C:4]([CH3:31])[C:3]=1[CH3:32].C(O)C.C(O)(=O)C.[OH-].[Na+]>[C].[Pd].O>[NH2:1][C:2]1[CH:29]([CH3:30])[CH:6]2[CH2:7][C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH:28]=[CH:27][N:26]=[CH:25]5)=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)([CH3:10])[O:9][C:5]2=[C:4]([CH3:31])[C:3]=1[CH3:32]
Reactant: CC1=C(N)C(C)C2CC(C)(CC3=CCN(c4ccc(-n5ccnc5)cc4)CC3)OC2=C1C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC1=C(N)C(C)C2CC(C)(CC3CCN(c4ccc(-n5ccnc5)cc4)CC3)OC2=C1C
Temperature: 50 °C
Reaction time: 7 h
Yield: 86.3 %

Procedure:
In an autoclave, to 0.45 g of 4-(±)-(5-amino-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-1-(4-imidazol-1-ylphenyl)-1,2,3,6-tetrahydropyridine and 0.1 g of 10% palladium carbon, 5 ml of ethanol and 5 ml of acetic acid were added, followed by stirring at 50° C. under a hydrogen pressure of 10 kg/cm2 for 7 hours. The reaction solution was poured into water, neutralized with 1N sodium hydroxide solution and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the resulting crystal was washed with hexane and then dried to obtain 0.39 g of the objective product (mp: 170-172° C.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[NH:11][C:12]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1.[CH2:22]([O:24][C:25]([CH2:27][CH2:28][CH2:29]Br)=[O:26])[CH3:23].O>CN(C)C=O>[CH2:22]([O:24][C:25]([CH2:27][CH2:28][CH2:29][N:14]1[C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:12]=2[N:11]=[C:10]1[CH2:9][O:8][C:7]1[CH:20]=[CH:21][C:4]([Cl:3])=[CH:5][CH:6]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21
Temperature: 25 °C
Yield: 111.9 %

Procedure:
A sodium hydride solution (60% in oil, 325 mg, 8.1 mmol) was washed with hexanes (2×50 ml) and then diluted with N,N-dimethylformamide (100 ml). At room temperature, under a nitrogen atmosphere, 2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (2.0 g, 7.3 mmol) was then added in one portion. The resulting mixture was then stirred at room temperature for thirty minutes, and then 3-(ethoxycarbonyl)propyl bromide (1.58 g, 8.1 mmol) in N,N-dimethylformamide (10 ml) was added dropwise. Upon completion of this addition, the reaction mixture was stirred for about six hours at a temperature of 70-80° C. The reaction mixture was then cooled to room temperature, poured into water (500 ml), and then extracted with ethyl acetate (500 ml). The organic fraction was washed once with water (500 ml) and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 3.16 grams of a semi-solid material. The crude material was firther purified by flash silica gel chromatography, eluting with a gradient solvent of methylene chloride to 1:1 methylene chloride:ethyl acetate. The fractions containing the desired title product were combined and concentrated in vacuo to yield 2.21 grams (78%) of a viscous yellow oil.
Reaction SMILES: [OH:1]O.[C:3]([CH2:6][S:7][C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([F:19])=[CH:14][CH:15]=2)[N:10]([CH3:20])[CH:9]=1)([OH:5])=[O:4]>C(O)(=O)C.O>[C:3]([CH2:6][S:7]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([F:19])=[CH:14][CH:15]=2)[N:10]([CH3:20])[CH:9]=1)=[O:1])([OH:5])=[O:4]
Reactant: Cn1cc(SCC(=O)O)c(=O)c2ccc(F)cc21
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(S(=O)CC(=O)O)c(=O)c2ccc(F)cc21
Temperature: 55 °C
Reaction time: 4 h

Procedure:
50% hydrogen peroxide (57ml, 33.6 mg, 0.988 mmol) was added to a solution of 3-carboxymethylthio-7-fluoro-1-methyl-4-quinolone (4) in acetic acid (3.6 ml) at 60° C. and the mixture was stirred at 55° C. for 4 h. The hot mixture was diluted with water (12ml) and cooled to 0° C. A white solid that precipitated was filtered off and dried under high vacuum. The yield of 3-Carboxymethylsulfinyl-7-fluoro-1-methyl-4-quinolone was 185 mg (72.7%) (5).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([CH3:14])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([CH3:14])[C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(F)c(F)c(F)c(F)c1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(F)c(F)c(F)c(F)c1C(=O)Cl
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A solution of 8.2 g (39.4 mmol) of 2,3,4,5-tetrafluoro-6-methylbenzoic acid, 6.0 g (47.2 mmol) of oxalyl chloride, and 100 mL of dichloromethane was treated with three drops of DMF. The solution was stirred for 3 hours, then concentrated to give 8.8 g of the title compound as a yellow liquid. The product was used as is in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:24])[O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([O:53][C:54](=[O:65])[CH2:55][CH2:56][C:57]1([C:62](O)=[O:63])[CH2:61][CH2:60][CH2:59][CH2:58]1)([CH3:52])([CH3:51])[CH3:50].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:13]1[C:12]2[CH:11]([CH2:10][O:9][C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:62]([C:57]3([CH2:56][CH2:55][C:54]([O:53][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:65])[CH2:61][CH2:60][CH2:59][CH2:58]3)=[O:63])=[O:24])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Reactant: NCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
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: CC(C)(C)OC(=O)CCC1(C(=O)NCCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1
Reaction time: 0.17 h
Yield: 124.7 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl 5-aminopentylcarbamate (0.683 g, 2.105 mmol) in 15 ml DMF was added HATU (0.800 g, 2.105 mmol), 1-(3-tert-butoxy-3-oxopropyl)cyclopentanecarboxylic acid (0.425 g, 1.754 mmol) in 5 ml DMF, and DIEA (1.532 mL, 8.77 mmol). The solution was stirred for 10 minutes and material purified by HPLC using a gradient of 0-50% acetonitrile in DCM. Solvents were removed under reduced pressure to give 1.2 g crude tert-butyl 3-(1-(5-(((9H-fluoren-9-yl)methoxy)carbonylamino)-pentylcarbamoyl)cyclopentyl)propanoate. The crude material was dissolved in 20 ml DCM and 10 ml TFA was added to remove t-Bu group. Solvent was removed under reduced pressure and material purified by reverse phase chromatography to give 3-(1-(5-(((9H-fluoren-9-yl)methoxy)carbonylamino)pentylcarbamoyl)cyclopentyl)propanoic acid (16 mg, 0.032 mmol, 1.852% yield).