Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[N:16]1([CH2:22][CH2:23]Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCOCC.O>[C:3]1([CH:13]([CH2:23][CH2:22][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: N#CCc1cccc2ccccc12
Reactant: ClCCN1CCCCC1
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N#CC(CCN1CCCCC1)c1cccc2ccccc12
Reaction time: 5 h

Procedure:
8.2 g of sodium amide are added in small quantities on a solution of 33.4 g of 1-naphthyl acetonitrile in 450 ml of anhydrous ether. The mixture is heated for 2 hours to reflux, then 29.5 g of 2-piperidino-1-chloroethane are added, a heating to reflux is repeated for 5 hours. The mixture is then cooled, poured in water, and the organic phase is extracted 3 times with 600 ml of hydrochloric acid at 10%. The aqueous phase is washed with ether and neutralized with soda at 30%. The decanting oil is extracted, washed with sodium chloride-saturated water and dried over magnesium sulphate. After evaporation of the solvent, the resulting oil is distilled under reduced pressure (vane pump).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[CH2:13][NH2:14].Cl[S:16]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:14]([CH2:13][C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[S:16]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1cc(OC)c(CN)c(OC)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: BrCc1ccccc1
Product: COc1cc(OC)c(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)O)cc2)c(OC)c1

Procedure:
Prepared as in example 5-10 from (2,4,6-trimethoxyphenyl)methanamine, methyl 4-(chlorosulfonyl)benzoate (Example 5-10c) and benzyl bromide. MS (M−H, 470.10); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.45 (s, 6H), 3.69 (s, 3H), 4.26 (s, 2H), 4.28 (s, 2H), 5.98 (s, 2H), 7.11-7.26 (m, 5H), 7.82 (d, J=8.0 Hz, 2H), 8.07 (d, J=8 Hz, 2H), 13.49 (s, 1H). Elemental analysis (found, %): C, 61.05; H, 5.49; N, 2.98. (calculated, %): C, 61.13; H, 5.34; and N, 2.97.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C[Si]([C:14]#[CH:15])(C)C.C(N(CC)CC)C>CN(C)C=O>[C:14]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])#[CH:15]
Reactant: COc1ccccc1I
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccccc1OC
Yield: 50.9 %

Procedure:
2-Iodoanisole (10.5 g) and trimethylsilylacetylene (10.3 g) were reacted in dimethylformamide (50 ml), in the presence of dichloro-bis-triphenylphosphine palladium (1.0 g), cuprous iodide (0.5 g) and triethylamine (15 ml) in nitrogen atmosphere at 50° C. for 12 hr. The resulting reaction solution was evaporated, and to the resulting residue was added ethyl acetate and water. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was dissolved in methanol (100 ml), a 5N aqueous solution of sodium hydroxide (20 ml) was added thereto, and then reacted at 60° C. for 1 hr. The reaction solution was evaporated, and to the resulting residue was added ether and water. The resulting ether layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a pale yellow oil (3.02 g, yield; 51%). (232-2) 2-[2-Methoxyphenyl)ethynyl]-5-methoxybenzaldehyde
Reaction SMILES: S(Cl)(Cl)=O.FC(F)(F)[C:7]1[CH:8]=[C:9]([CH:13]=[C:14](C(F)(F)F)[CH:15]=1)[C:10](O)=[O:11].CC1C=CC([NH2:27])=CC=1[N+]([O-])=O.C(N(CC)CC)C.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)C(Cl)=O>C(Cl)(Cl)Cl>[C:10]([NH2:27])(=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Agent: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Thionyl chloride (576.0 g, 4.8 mol) was added over a period of 15 min to a solution of 3,5-bis trifluoro methyl benzoic acid (Lancaster) (250.0 g, 0.97 mol) in chloroform (2.5 L) at room temperature. The reaction mixture was heated to reflux temperature for 1 hour. The excess of thionyl chloride was removed by co-distillation with chloroform under reduced pressure. After the end of the distillation, the resulting 3,5-bis trifluoro methyl benzoyl chloride was cooled down to room temperature and dissolved in 400 ml chloroform. A solution of 4-methyl-3-nitroaniline (92.0 g, 0.60 mol) in chloroform (1.2 L) was cooled to −5° C. and triethyl amine (304.8 g, 3.0 mol) was added. 3,5-bis trifluoro methyl benzoyl chloride in chloroform was added drop wise at −5° C. over a period of 60-75 min. The resulting suspension was stirred for 1 hr at −5° C. The suspension was distilled to a residual volume of 800 ml and filtered, washed with chilled chloroform (200 ml) and dried in vacuum to give 160.0 g of novel (3,5-bis trifluoromethyl)-N-(4-methyl-3-nitrophenyl)-)-benzamide (68%) as cream colored crystals (98.2% purity by HPLC) MR-123-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Br.Br.Br[CH2:25][C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:25][C:26]2[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Nc1ncc(CBr)c(N)n1
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(Cc2cnc(N)nc2N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
A solution of 3.2 g (0.017 mol) of 1-(2-methoxy-phenyl)-piperazine in 100 ml of tetrahydrofuran was treated with 11.6 ml (0.084 mol) of triethylamine and 6.1 g (0.017 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 16 hours. The suspension obtained was suction filtered and the filtrate was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent and digested in diethyl ether. 2.0 g (38%) of 5-[4-(2-methoxy-phenyl)-piperazin-1-ylmethyl]-pyrimidine-2,4-diamine were obtained as white crystals; m.p. 195°-196°.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.[Cl:25][CH:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27](Cl)=[O:28]>C(OCC)(=O)C>[F:18][C:15]([F:16])([F:17])[C:11]1[CH:10]=[C:9]([NH:8][C:27](=[O:28])[CH:26]([Cl:25])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
A toluene [350 milliliters (mL)] solution of 3-aminobenzotrifluoride [35.5 grams (g) 0.22 mol] and pyridine (19.1 grams, 0.24 mol) was cooled in an ice bath. 2-Chloro-2-phenylacetyl chloride (45.8 grams, 0.24 mol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2 ×200 mL) and dried with magnesium sulfate. The solvent was removed in a rotary evaporator to provide the desired N-(3-trifluoromethylphenyl)-2-chloro-2-phenylacetamide (61.6 grams, 89% yield) whose structure was confirmed by nuclear magnetic resonance, infra-red spectroscopy, and mass spectroscopy analysis.
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([NH2:21])=[NH:20])[CH:13]=[CH:12]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:22](N(CC)CC)C.[N:29]1[CH:34]=[CH:33][CH:32]=CC=1>O>[CH2:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]3[N:21]=[CH:22][C:33]([C:34]#[N:29])=[CH:32][N:20]=3)[CH:15]=2)[CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: c1ccncc1
Reactant: CCN(CC)CC
Reactant: CCCCCCCc1ccc2cc(C(=N)N)ccc2c1
Agent: Cl
Solvent: O
Product: CCCCCCCc1ccc2cc(-c3ncc(C#N)cn3)ccc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
6-Heptyl-2-naphthalenecarboxamidine hydrochloride (4.0 g, 13 mmols), α-cyano-β-dimethylaminoacrolein (1.6 g, 13 mmols), triethylamine (30 ml) and pyridine (30 ml) were placed in a flask, followed by heating under reflux with stirring for 6 hours, cooling down to room temperature, and pouring the reaction mixture into water (500 ml) to deposit white solids, which were then separated by filtration and dissolved in toluene (100 ml), followed by washing the toluene layer with water, drying over anhydrous sodium sulfate and distilling off toluene under reduced pressure to obtain solids, which were recrystallized from a mixed solvent of ethanol-ethyl acetate (1:1) to obtain the objective 2-heptyl-6-(5-cyano-2-pyrimidinyl)naphthalene (3.0 g, 9.2 mmols) (yield: 70%). This product exhibited a liquid crystalline phase, and its crystalline-smectic phase transition point (C-S point) was 124.6°-125.6° C.; its smectic-nematic phase transition point (S-N point), 153.9°-154.1° C.; and its nematic-isotropic phase transition point (N-I point), 163.5°-163.7° C.
Reaction SMILES: C(O[C:4]1[C:8]([O:9][CH2:10][CH3:11])=[N:7][S:6](=[O:12])[N:5]=1)C.[NH2:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[C:16]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:15]=1>O1CCCC1.CO>[CH2:10]([O:9][C:8]1[C:4]([N:31]2[CH2:32][CH2:33][N:28]([C:16]3[N:15]=[C:14]([NH2:13])[C:23]4[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=4)[N:17]=3)[CH2:29][CH2:30]2)=[N:5][S:6](=[O:12])[N:7]=1)[CH3:11]
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CCOC1=NS(=O)N=C1OCC
Solvent: CO
Solvent: C1CCOC1
Product: CCOC1=NS(=O)N=C1N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.9 g (10 mMoles) of 3,4-diethoxy-1,2,5-thiadiazole-1-oxide are added to 2.9 g (10 mMoles) of 4-amino-6,7-dimethoxy-2-piperazinoquinazoline dissolved in 50 ml of tetrahydrofuran and 10 ml of methanol, followed by stirring for 5 hours at room temperature. The solid accumulating is separated off and recrystallized from 15 ml of dimethyl formamide and 10 ml of ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[C:14](Cl)(=O)[C:15](Cl)=O.C(O)C>ClCCl.CN(C)C=O>[CH2:14]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:12])[C:10]([F:11])=[C:2]([Cl:1])[C:3]=1[F:13])[CH3:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cc(F)c(F)c(Cl)c1F
Reaction time: 0.75 h
Yield: 100.6 %

Procedure:
To a solution of 3-chloro-2,4,5-trifluorobenzoic acid (Example 20, 4.90 g, 23.3 mmol) in dichloromethane (50 mL) is added oxalyl chloride (5.1 mL, 58.2 mmol) and N,N-dimethylformamide (1 drop). After 45 minutes, the reaction mixture is concentrated under vacuum. The resulting residue is dissolved in dichloromethane (50 mL) and treated with ethanol (10 mL, 172 mmol). After 30 minutes, the reaction mixture is diluted with dichloromethane and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound (5.59 g). 1H NMR (CDCl3): δ 7.76-7.68 (m, 1H), 4.40 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([O:14][C:15]([NH:17][C@H:18]([C:27](O)=[O:28])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:30]([O:34][C:35](=[O:50])[C@H:36]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:41][CH:40]=1)[NH2:37])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:50])[C@H:36]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:41][CH:40]=1)[NH:37][C:27](=[O:28])[C@H:18]([CH2:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[NH:17][C:15]([O:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:16])([CH3:32])([CH3:33])[CH3:31].[NH:37]1[CH2:36][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OC1c2ccccc2-c2ccccc21)C(=O)O
Product: C1CCNCC1
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)OC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C

Procedure:
N-[(9H-fluoren-9-yloxy)carbonyl]-3-(t-butoxycarbonyl)-L-alanine and 3-(p-t-butoxyphenyl)-L-alanine t-butyl ester were coupled to give N-[N-[(9H-fluoren-9-yloxy)carbonyl] -3-(t-butoxycarbonyl)-L-alanyl]-3-(p-t-butoxyphenyl)-L-alanine t-butyl ester and 5 ml of piperidine and the reaction solution was evaporated. The residue was suspended in methanol and insoluble material was filtered off. The filtrate was evaporated and chromatographed on silica gel using ethyl acetate to yield 2 g of 3-(t-butoxyphenyl)-N-[3-(p-t-butoxy-carbonyl)-L-alanyl]-L-alanine t-butyl ester.
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:21]([CH3:22])=[CH:20][NH:19][N:18]=1.[CH3:23]C1C(C2C=CC=CC=2)=NNC=1>>[CH2:8]([CH:2]([N:19]1[CH:20]=[C:21]([CH3:22])[C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])=[N:18]1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[CH3:23]
Reactant: CC(Cl)C(=O)N(C)C
Reactant: COc1ccccc1-c1n[nH]cc1C
Reactant: Cc1c[nH]nc1-c1ccccc1
Product: CCC(C(=O)N(C)C)n1cc(C)c(-c2ccccc2OC)n1

Procedure:
Using the procedure of Example 1, but substituting 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide and 3-(o-methoxyphenyl)-4-methylpyrazole for 4-methyl-3-phenylpyrazole there is obtained α-ethyl-3-(o-methoxyphenyl)-N,N,4-trimethylpyrazole-1-acetamide, m.p. 79°-81° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].[CH2:11]=O.C[O-].[Na+].[BH4-].[Na+]>CO.C(OCC)(=O)C>[CH3:11][NH:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[CH3:1]
Reactant: C=O
Reactant: COc1ccc(N)c(C)c1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNc1ccc(OC)cc1C
Temperature: 50 °C
Yield: 91.1 %

Procedure:
A suspension of [2-methyl-4-(methyloxy)phenyl]amine (5 ml, 39.2 mmol), paraformaldehyde (5.88 g, 196 mmol), and sodium methoxide (10.58 g, 196 mmol) in methanol (100 ml) was maintained at 50° C. for 5 hours, cooled, and sodium borohydride (7.41 g, 196 mmol) was added portionwise. The resulting suspension was re-heated to 50° C. and maintained for 16 hours. The reaction was cooled, poured into ethyl acetate/saturated sodium bicarbonate, and the organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford N,2-dimethyl-4-(methyloxy)aniline (5.40 g, 35.7 mmol, 91% yield) as a pale orange oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.55-6.68 (m, 2 H), 6.34-6.40 (m, 1 H), 4.47-4.66 (m, 1 H), 3.62 (s, 3 H), 2.66 (d, J=5.0 Hz, 3 H), 2.04 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][C:22]([NH:29][C:30]([O:32][CH3:33])=[O:31])([CH3:28])[C:23](OCC)=[O:24].[BH4-].[Li+].C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][C:22]([NH:29][C:30]([O:32][CH3:33])=[O:31])([CH3:28])[CH2:23][OH:24]
Reactant: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl)NC(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)NC(C)(CO)CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl
Yield: 90.2 %

Procedure:
To a solution of the compound of Example 54 (15.6 g) in THF (249 mL) was added under ice cooling lithium borohydride (3.75 g), and then ethanol (16.6 mL) was added dropwise. The resultant solution was then stirred for 1 hour under ice cooling. To the reaction solution was added 10% aqueous citric acid, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the target product (12.9 g) as a colorless oil.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2](C=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:15][C@H:16]1[CH2:20][CH2:19][C@@H:18]([C:21]([OH:23])=[O:22])[CH2:17]1.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C.[Cl-].[Na+]>[C:12]1([CH2:24][NH:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([C:21]([OH:23])=[O:22])[CH2:17]2)[CH:11]=[CH:10][C:9]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: N[C@H]1CC[C@@H](C(=O)O)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1CC[C@H](NCc2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Biphenyl carboxaldehyde (2.82 g, 15.5 mmol) was added to a stirred solution of (1R,3S)-3-aminocyclopentanecarboxylic acid (2.0 g, 15.5 mmol) in anhydrous methanol (50 mL) and acetic acid (2 mL). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (6.57 g, 31 mmol) was added portion wise over 10 minutes and the reaction was stirred at room temperature for 4 hours, diluted with saturated aqueous sodium chloride, and extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give crude (1R,3S)-3-(biphen-4-ylmethyl-amino)-cyclopentane carboxylic acid, which was used in the next step without further purification; m/z for C19H21NO2 expected 295.2. found 318.1 (M+Na)+, 296.3 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][NH:9][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)CCCCCCBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCNCCc1ccccc1
Yield: 26.2 %

Procedure:
To a mixture of 2-penylethylamine (1.09 g, 9 mmol) and triethylamine (1.37 g, 13.5 mmol) in toluene (50 mL) was added methyl 7-bromoheptanoate (2.0 g, 9 mmol) and refluxed overnight. The reaction mixture was filtered and concentrated. Flash column chromatography over silica gel using 100% ethyl acetate yielded a yellow oil (0.62 g, 20%) NMR (250 MHz, CDCl3), 1.12-1.40 (4H, m), 1.40-1.72 (4H, m), 2.29 (2H, t), 2.63 (2H, t), 2.75-2.96 (4H, m), 2.96-3.1 (1H, br s), 3.66 (3H, s), 7.00-7.3 (5H, m).
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1)[CH2:2][CH3:3].[C:15]1([CH3:26])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[N:23]=[C:24]=[S:25]>CO.O>[CH2:12]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:24]([NH:23][C:16]2[C:15]([CH3:26])=[CH:20][C:19]([CH3:21])=[CH:18][C:17]=2[CH3:22])=[S:25])[CH:6]=1)[CH2:13][CH3:14]
Reactant: Cc1cc(C)c(N=C=S)c(C)c1
Reactant: CCCN(CCC)c1ccnc(N)c1
Solvent: O
Solvent: CO
Product: CCCN(CCC)c1ccnc(NC(=S)Nc2c(C)cc(C)cc2C)c1
Yield: 21.7 %

Procedure:
To 0.106 g (0.0.55 mmol) of N4,N4-dipropylpyridine-2,4-diamine in 10 mL of methanol was added 0.117 g (0.66 mmol) of mesitylisothiocyanate. The mixture was heated at reflux for 24 h, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo and the resulting crude solid was purified by flash chromatography eluting with a 85% hexanes/ethyl acetate mixture to give 0.044 g (22%) of the title compound as a white solid.
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[CH2:9]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH3:10].Br[CH2:19]C(C)=C>C1COCC1>[CH2:9]([O:11][C:12](=[O:17])[CH:13]([CH2:8][CH:6]=[CH2:7])[CH2:14][C:15]([CH3:19])=[CH2:16])[CH3:10]
Reactant: C=CCCC(=O)OCC
Reactant: C=C(C)CBr
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(CC(=C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a cold (−78° C.) stirred solution of LDA (generated from DIPA (1.42 mL, 10.14 mmol), BuLi (5.85 mL, 9.36 mmol) in THF at −78° C. for 20 min) in THF (31 mL) was added a solution of Pent-4-enoic acid ethyl ester (1.0 g, 7.8 mmol, 1.2 eq.) in THF (9.0 mL). After stirred for 1 h, neat 3-Bromo-2-methyl-propene (2.03 g, 15.0 mmol, 1.51 mL) was added and slowly warmed up to room temperature for overnight. The reaction mixture was then quenched with saturated NH4Cl solution, extracted with ether, washed with brine and dried. Evaporation of the solution furnished the 2-Allyl-4-methyl-pent-4-enoic acid ethyl ester (1.45 g, 100%) as an oil which was used in the next step without purification. 1H NMR (400 MHz, CDCl3), 5.78-5.71 (m, 1H), 5.05 (d, J=18.6 Hz, 1H), 5.02 (d, J=9.4 Hz, 1H), 4.76 (brs, 1H), 4.70 (s, 1H), 4.11 (dq, J=7.2, 1.0 Hz, 2H), 2.66-2.13 (m, 5H), 1.72 (s, 3H), 1.23 (dt, J=7.2, 1.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>CN(C=O)C.C(OCC)(=O)C>[CH:21]1([CH2:20][O:10][C:9]2[C:8]([O:11][CH3:12])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH2:23][CH2:22]1
Reactant: COc1cc(C=O)cc(F)c1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)cc(F)c1OCC1CC1
Temperature: 70 °C

Procedure:
To a solution of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (5.00 g) in DMF (50 mL) were added potassium carbonate (6.09 g) and (bromomethyl)cyclopropane (3.42 mL), and the mixture was stirred with heating at 70° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was 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 (6.59 g).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]([O:14][C@H:15]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][N+:20]([O-:24])=[CH:19][C:18]=2[Cl:25])=[O:13])[CH2:9]1)=O)(C)(C)C.Cl.C(OCC)C.C(#N)C>C(OCC)(=O)C>[ClH:23].[Cl:25][C:18]1[CH:19]=[N+:20]([O-:24])[CH:21]=[C:22]([Cl:23])[C:17]=1[CH2:16][C@H:15]([O:14][C:12]([CH:10]1[CH2:11][NH:8][CH2:9]1)=[O:13])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)C2CN(C(=O)OC(C)(C)C)C2)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)C2CNC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 200.5 %

Procedure:
To a stirred solution of (S)-4-(2-((1-(tert-butoxycarbonyl)azetidine-3-carbonyl)oxy)-2-(3,4-dimethoxyphenyl)ethyl)-3,5-dichloropyridine 1-oxide (105 mg, 0.2 mmol) in ethyl acetate (0.5 mL) was added a 2M solution of HCl in diethyl ether (1.5 mL, 3 mmol). The mixture was allowed to stir at room temperature for 4 hours and then acetonitrile (5 mL) was added. The mixture was allowed to stir at room temperature for 3 hours. The solid was removed by filtration, washed with diethyl ether and dried to afford the title compound as a yellow solid (93 mg, 95%).