Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].[NH4+].[Cl-].I[CH2:16][C:17]([CH3:19])=[CH2:18]>C1COCC1.[Zn]>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)([OH:5])[CH2:18][C:17]([CH3:19])=[CH2:16]
Reactant: C=C(C)CI
Reactant: O=C(CCCl)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C(C)CC(O)(CCCl)c1ccc(F)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 3-chloro-1-(4-fluorophenyl)-propan-1-one (18.6 g, 0.1 mol) in THF (50 mL) was added to a well-stirred suspension of zinc power (13 g, 0.2 mol) in a mixture of aqueous saturated NH4Cl solution (260 mL) and THF (65 mL). A solution of 3-iodo-2-methylprop-1-ene (36.4 g, 0.2 mol) in THF (50 mL) was added dropwise. The reaction mixture was mildly exothermic, and began to reflux spontaneously. After the refluxing had ceased, the mixture was stirred for 1 h. TLC showed the 3-chloro-1-(4-fluorophenyl)propan-1-one not reacted completely. A solution of 3-iodo-2-methylprop-1-ene (18.2 g, 0.1 mol) in THF (30 mL) was added, and the mixture was stirred at rt overnight. The mixture was extracted with EtOAc (2×500 mL). The combined organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with petroleum ether/EtOAc 50:1→30:1→5:1, to give 1-chloro-3-(4-fluorophenyl)-5-methylhex-5-en-3-ol (17 g, yield 76%) as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[NH2:22].N1C=CC=CC=1>ClCCl>[CH3:29][O:28][C:24]1[CH:23]=[C:21]([NH:22][C:8](=[O:10])[CH2:7][CH:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)[CH:20]=[C:19]([O:18][CH3:17])[C:25]=1[O:26][CH3:27]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)CC1CCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(NC(=O)CC2CCC(=O)C2)cc(OC)c1OC
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 129.1 %

Procedure:
To a solution of 1.0 g (7 mmol) of 3-oxocyclopentyl acetic acid in dichloromethane (18 mL) and DMP (1 mL), was added 0.68 mL (7.7 mmol) oxalyl chloride. After 30 min, the solvent was removed in vacuo. The residue was dissolved in dichloromethane (20 mL), cooled to 0-5° C., and 1.29 g of 3,4,5-trimethoxyaniline (0.63 mmol) was added followed by 0.68 mL of pyridine (8.4 mmol). After 15 min, the reaction was allowed to warm to ambient temperature. After 2 h, the reaction was rinsed with 1N HCl, followed by aq. sodium bicarbonate, and water (3×). The organic layer was dried, the solvent removed in vacuo and the residue chromatographed on a silica gel with 2% methanol in methylene chloride to yield 0.25 g of the title compound. MS(ES+)m/z=308.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[F:29][C:30]1[CH:53]=[CH:52][C:33]([CH2:34][N:35]2[CH2:39][CH2:38][N:37]([C:40]3[S:44][C:43]([C:45]([O:47]CC)=[O:46])=[C:42]([CH3:50])[CH:41]=3)[C:36]2=[O:51])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:34][N:35]2[CH2:39][CH2:38][N:37]([C:40]3[S:44][C:43]([C:45]([OH:47])=[O:46])=[C:42]([CH3:50])[CH:41]=3)[C:36]2=[O:51])=[CH:52][CH:53]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)cc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Yield: 90 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylate, the title compound was obtained as a colorless solid in 90% yield: 1H NMR (300 MHz, DMSO-d6) δ 12.34 (br s, 1H), 7.35 (dd, J=8.6, 5.6 Hz, 2H), 7.19 (t, J=8.6 Hz, 2H), 6.29 (s, 1H), 4.39 (s, 2H), 3.87-3.78 (m, 2 H), 3.48-3.40 (m, 2H), 2.40 (s, 3H); MS (ES+) m/z 335.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-])=O)=[C:6]([CH2:8][CH:9]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.CO.O.[OH-].[NH4+]>C(OCC)(=O)C>[NH2:27][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[CH2:8][CH:9]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1
Reactant: COC(=O)C(C(=O)OC)C(Cc1cc(Cl)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(C(=O)OC)C(Cc1cc(Cl)ccc1N)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a refluxing mixture of [2-(5-chloro-2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (40 g, 95.0 mmole) and hydrated ferrous sulfate (184.5 g, 0.663 mole) in a (1:10 solution of methanol:water (1.2 L) was added concentrated ammonium hydroxide (142.5 ml) over a 30 minute period. The reaction was stirred at reflux for 20 minutes then cooled to room temperature. Ethyl acetate and Celite were added and the mixture was filtered through Celite. The filtrate was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The product was recrystallized from isopropyl alcohol to yield 28.22 g of the title compound, melting point 114°-116° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2ccccc2)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of Example 17D (202.1 mg, 0.64 mmol) and triethylamine (0.14 mL) in anhydrous dichloromethane (5 mL) was added benzoyl chloride (0.08 mL, 0.64 mmol) dropwise. The mixture was allowed to stir for 6 hours at room temperature and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (30 mL) and H2O (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to an oil, which was chromatographed using a Biotage 40M eluting with 20% hexane/80% ethyl acetate to provide (2S, 4R)-4-(benzoylamino-methyl)-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a brown oil. MS (ESI) m/e 420 (M+H)+, 418 (M−H)−.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[NH4+].[Cl-]>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)([OH:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1ccc(Sc2ccccc2Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(Sc2ccccc2C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of BuLi (2.5 M in hexane, 12.0 ml, 30 mmol) was slowly added to a stirred solution of 1-bromo-2-(4-methylphenylsulfanyl)benzene (30 mmol) in dry THF (75 ml) under Argon at −78° C. The solution was stirred for 10 min before 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.98 g, 30 mmol) was added in one portion. The solution was allowed to warm up to room temperature and then stirred for 3 h. Saturated aqueous NH4Cl (150 ml) was added and the solution was extracted with ethylacetate (150 ml). The organic phase was washed with brine, dried (MgSO4) and the solvent was evaporated in vacuo. Crude 1 was purified by flash chromatography on silica gel (eluent: Ethylacetat/heptane 20:80) to produce the target compound as a white foam. LC/MS (m/z) 399.3 (MH+); RT=3.82; purity (UV, ELSD): 98%, 100%; yield: 5.02 g (42%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([OH:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.CN(C=O)C.N1C=CN=C1.[CH:27]([Si:30](Cl)([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28]>O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([OH:15])=[CH:11][C:12]([O:14][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:27]([CH3:29])[CH3:28])=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(O)cc(O)c12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1csc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(O)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of methyl(4,6-dihydroxy-1-benzothiophen-3-yl)acetate (7.7 g) and DMF (dry) (150 mL) was added imidazole (4.40 g) at room temperature, and the mixture was added slowly triisopropylsilyl chloride (7.61 mL) over a period of 20 min, and the mixture was stirred at room temperature for 48 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (8.10 g).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[CH3:8][O:9][C:10]1[CH:46]=[CH:45][C:13]([C:14]([O:29][CH2:30][C@H:31]2[O:35][C@@H:34]([N:36]3[CH:43]=[CH:42][C:40](=[O:41])[NH:39][C:37]3=[O:38])[CH2:33][C@@H:32]2[OH:44])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:46]=[CH:45][C:13]([C:14]([O:29][CH2:30][C@H:31]2[O:35][C@@H:34]([N:36]3[CH:43]=[CH:42][C:40](=[O:41])[N:39]([CH2:6][CH2:5][CH2:4][CH2:3][C:2]#[CH:1])[C:37]3=[O:38])[CH2:33][C@@H:32]2[OH:44])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: C#CCCCCO
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: C#CCCCCn1c(=O)ccn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)O2)c1=O
Yield: 86 %

Procedure:
5-Hexynol was allowed to react with 2′-deoxy-5′-O-(4,4′-dimethoxytrityl)uridine under Mitsunobu conditions described in example 1. Purification on silica gel (eluent diethyl ether) yielded the title compound as a solid (86%) Compound 9:
Reaction SMILES: N[C:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[CH:3][C:4]#[N:5].Cl.C[OH:13]>>[O:13]=[C:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH2:3][C:4]#[N:5]
Reactant: CO
Reactant: N#CC=C(N)c1ccsc1
Agent: Cl
Product: N#CCC(=O)c1ccsc1
Reaction time: 3 h

Procedure:
A 1.2 g. portion of β-amino-3-thiopheneacrylonitrile is added to 10 ml. of 1 N hydrochloric acid. A 40 ml. portion of methanol is added and the mixture is stirred for 3 hours. The mixture is evaporated in vacuo to a residue which is dissolved in 35 ml. of hot methanol and treated with charcoal. After cooling, petroleum ether is added, the mixture is filtered and the collected solid is discarded. The filtrate is evaporated and the residue is dissolved in 35 ml. of hot isopropanol and the insoluble material is filtered and discarded. The filtrate is cooled and the solid is collected giving the desired produce as white plates, mp. 87°-88° C.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH:11]([NH:15][C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32](=O)[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH:11]([N:15]([CH2:32][CH3:33])[C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1C[C@@H](C)N(Cc2ccccc2)[C@@H](C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a stirred solution of methyl 3-{[(2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-yl]amino}-2-methyl-5-(trifluoromethyl)benzoate (223 mg, 0.513 mmol) in chloroform (4 mL) and acetic acid (500 uL) was added acetaldehyde (1.0 ml) and stirred for 30 min at 0° C. Then sodium triacetoxyborohydride (343 mg, 1.54 mmol) was added to the reaction mixture at 0° C. The reaction mixture was stirred at 23° C. for 4 hours. Then the reaction mixture was quenched with aq. NaHCO3 until pH8-9. The content was extracted with ethylacetate. The organic layer was washed with brine. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethylacetate=4/1 to 1/2) to give the titled compound as a colorless oil. (105.5 mg, 44% yield). MS (ES) [M+H] 463.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[NH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>COCCOCCOC>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[N:4][CH:3]=[C:2]2[NH:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)CN
Reactant: FC(F)(F)c1ccc2nncc(Cl)c2c1
Solvent: COCCOCCOC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNc1cnnc2ccc(C(F)(F)F)cc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8 mL vial, was placed a solution of 4-chloro-6-(trifluoromethyl)cinnoline (as prepared in the previous step, 260 mg, 1.12 mmol, 1.00 equiv) in 2-methoxyethyl ether (2 mL), tert-butyl 2-aminoacetate (187 mg, 1.12 mmol, 1.10 equiv) and triethylamine (339 mg, 3.36 mmol, 3.00 equiv). The reaction mixture was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of 4 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate, and the combined organic layers washed with 2×10 mL of brine, dried (Na2SO4), and concentrated under vacuum. The title compound was obtained as a yellow solid.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][C:7]=1N)[CH:3]([CH3:5])[CH3:4].N([O-])=O.[Na+].[F:21][B-](F)(F)F.[NH4+]>O>[F:21][C:7]1[CH:9]=[C:10]([CH2:13][CH:14]([CH3:15])[CH3:16])[CH:11]=[CH:12][C:6]=1[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)Cc1ccc(CC(C)C)c(N)c1
Reactant: F[B-](F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [NH4+]
Solvent: O
Product: CC(C)Cc1ccc(CC(C)C)c(F)c1

Procedure:
To 124 parts of 6N hydrochloric acid is added 48.8 parts of 2,5-diisobutylaniline. The mixture is cooled to 0° and a cold solution of 17.3 parts of sodium nitrite in water is added slowly, keeping temp. at 0°. A cold solution of 35 parts of ammonium fluoroborate in 120 parts of water is added with vigorous stirring. After one half hour, the precipitate is collected, washed with 25 parts cold 5% ammonium fluoroborate solution, 30 parts cold methanol and ether. The 2,5-diisobutylbenzenediazonium fluoroborate is air dried. The salt is placed in a flask with tube connecting to a second cooled flask and heated until decomposition begins. Sufficient heat to maintain gentle decomposition is continued. When decomposition is complete, the 2-fluoro-1,4-diisobutylbenzene is taken up in ether, washed with dilute sodium hydroxide and water and dried. Removal of the ether gives 2-fluoro-1,4-diisobutylbenzene which can be purified by distillation under reduced pressure.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:14][C:15]#[N:16].[I-].[Na+]>C(#N)C.C(=O)([O-])[O-].[K+].[K+]>[CH2:1]([N:8]([CH2:14][C:15]#[N:16])[C:9]([CH3:12])([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: CC(C)(C)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)N(CC#N)Cc1ccccc1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
Benzyl(tert-butyl)amine (10.0 g, 61.3 mmol) was dissolved in acetonitrile (100 ml), and bromoacetonitrile (4.5 ml, 64.6 mmol), potassium carbonate (16.9 g, 122.3 mmol) and sodium iodide (9.2 g, 61.4 mmol) were successively added with stirring at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with saturated aqueous potassium carbonate solution, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure, and the obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (10.8 g, yield 87%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:39](=O)[CH:40]([CH3:42])[CH3:41]>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Reactant: CC(C)C=O
Product: CC(C)CN[C@@H](Cc1ccc2ccccc2c1)C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure F using isobutyraldehyde. The final product was obtained in 57% yield.
Reaction SMILES: [F:1][C:2]([F:15])([CH:12]([F:14])[F:13])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43](=[O:50])[CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:39][CH:38]=1.[H-].[Na+].C(Br)(Br)Br>C(Cl)(Cl)(Cl)Cl.COCCOC.O>[F:36][C:37]1[CH:38]=[CH:39][C:40]([C:43](=[O:50])[CH:44]([CH2:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][C:2]([F:15])([F:1])[CH:12]([F:13])[F:14])[CH:6]=2)[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:41][CH:42]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: Cc1cccc(OCC(F)(F)C(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [H-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: BrC(Br)Br
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OCC(F)(F)C(F)F)c1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a solution of 3-(2,2,3,3-tetrafluoropropyloxy)toluene (7.0 g, 31.5 mmol) in carbon tetrachloride (100 ml) were added N-bromosuccinimide (6.17 g, 34.7 mmol) and 2,2′-azobis(isobutyronitrile) (517 mg, 3.15 mmol) and the mixture was heated under reflux overnight. The insoluble material was filtered using celite and the filtrate was concentrated to prepare a bromo form. To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (5.96 g, 28.4 mmol) in 1,2-dimethoxyethane (60 ml) was added sodium hydride (60% in oil, 1.13 g, 28.4 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of the bromo form synthesized above in 1,2-dimethoxyethane (20 ml) and the reaction solution was stirred at room temperature for 1 hr. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from diisopropyl ether-hexane to give ethyl 3-(4-fluorophenyl)-3-oxo-2-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)propionate (5.63 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[CH:14]=[N:15]O.S(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]([CH:10]([CH3:11])[CH3:12])[CH3:9])[C:4](=[O:13])[C:3]=1[C:14]#[N:15]
Reactant: CC(C)[C@H](C)n1ccc(Cl)c(C=NO)c1=O
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CC(C)[C@H](C)n1ccc(Cl)c(C#N)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 4-chloro-3-((hydroxyimino)methyl)-1-((2S)-3-methylbutan-2-yl)pyridin-2(1H)-one obtained in Step D (23.2 g) in acetonitrile (300 mL) was added dropwise thionyl chloride (13.9 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and to the residue were added diisopropyl ether/ethyl acetate/hexane. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (14.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]([CH3:20])[CH2:11]1.N[C:22](N)=[O:23]>CC1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]([CH3:20])[CH2:11]3)[C:22](=[O:23])[NH:1][C:2]=2[CH:7]=1
Reactant: COC(=O)N1CCC(Nc2ccc(Cl)cc2N)CC1C
Reactant: NC(N)=O
Solvent: Cc1ccccc1
Product: COC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1C
Temperature: 160 °C

Procedure:
A mixture of 36 parts of methyl 4-(2-amino-4-chlorophenylamino)-2-methyl-1-piperidinecarboxylate and 14 parts of urea is stirred and heated in an oil-bath at 160° C. for 4 hours. After cooling, the reaction mixture is disslved in methylbenzene. The solution is washed successively three times with water, twice with a diluted hydrochloric acid solution and again three times with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silicagel, using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding methyl 4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-2-methyl-1-piperidinecarboxylate as an oily residue.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)O.[Cl:14]Cl>>[Cl:14][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: ClCl
Reactant: CCCCCC(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)CCCCCCl

Procedure:
135 parts by mass of the caproic acid were added to 1,000 parts by mass of 27N sulfuric acid saturated with chlorine and were reacted for 6 hours at 25° C. to obtain 87 parts by mass of 6-chlorocaproic acid.