Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][C:50]4[CH:52]=[CH:53][CH:54]=[C:48]([F:47])[CH:49]=4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc(F)c1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2cccc(F)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-fluoroaniline (Aldrich) to give the title product. LC-MS (ES+) 758 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]([OH:12])=[O:11])[NH2:9])=[CH:4][CH:3]=1.ClCCl.C[Si](C)(C)Cl.Cl.[OH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][N:31]=2)[N:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34]>C(N(CC)CC)C>[OH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][N:31]=2)[N:26]=[CH:25][C:24]=1[C:33]([NH:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:10]([OH:12])=[O:11])=[O:34]
Reactant: O=C(Cl)c1cnc2cccnc2c1O
Reactant: NC(C(=O)O)c1ccc(O)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(C(=O)O)c1ccc(O)cc1)c1cnc2cccnc2c1O

Procedure:
To a mixture of 1.35 g of DL- 2-p-hydroxyphenylglycine, 50 ml of anhydrous dichloromethane and 4.05 of triethylamine, 2.62 g of trimethylchlorosilane were added, and the resulting mixture was refluxed for 20 minutes. After the addition of 2.1 g of 4-hydroxy-1,5-naphthyridine-3-carbonyl chloride hydrochloride, the reaction was effected while cooling with ice for 4 hours. The reaction mixture was concentrated under reduced pressure, 50 ml of water were added to the residue, and the resulting mixture was adjusted to pH 1 with 4N hydrochloric acid. The precipitated crystals were collected by filtration, suspended in 50 ml of water and potassium carbonate was added thereto. After removal of insoluble materials by filtration, the filtrate was adjusted to pH 1. The precipitated crystals were collected by filtration, washed with water and dried to give 2.1 g of DL-α-(4-hydroxy-1,5-napthyridine-3-carboxamido)-p-hydroxyphenylacetic acid. M.P. 310° to 320°C (decomp.)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:8][CH:9]([NH+:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[C:24]([NH:26][C@H:27]([C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=1)[CH3:28])=[O:25])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO.[OH-].[Na+]>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:8][CH:9]([NH+:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[C:24]([NH:26][C@H:27]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=1)[CH3:28])=[O:25])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCC[NH+]2C(C)COc2ccccc2)cc1
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(COc1ccccc1)[NH+]1CCCC[C@@H]1C(=O)N[C@@H](C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve methyl 4-[(1S)-1-[[(2R)-1-(1-methyl-2-phenoxyethyl)piperidinium-2-carbonyl]amino]ethyl]benzoate trifluoroacetate (24 mg, 0.045 mmol) in THF (226 μL) and treat the mixture with methanol (226 μL) and sodium hydroxide (1 N aqueous solution, 170 μL, 0.17 mmol). Stir the mixture overnight at room temperature, then concentrate under reduced pressure to furnish a gummy solid. Subject the crude material to reverse-phase chromatography on C18 silica gel, eluting with 0.1% TFA in a gradient of 5% to 50% ACN/water to furnish two separate fractions, each containing a separate diastereomer of product. Concentrate each fraction under reduced pressure, dissolve each in a minimal volume of methanol, triturate each with diethyl ether (5 mL), and concentrate each under reduced pressure to furnish Isomer 1 (3.0 mg, 13% yield) and Isomer 2 (1.1 mg, 5% yield) of the title compound as white solids.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C:8]([C:10]1[S:11][C:12]([S:39][CH3:40])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH:31][C:32]([NH:34][CH2:35][CH2:36][C:37]#[N:38])=[O:33])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1SC(SC)=C(S(C2C=C(C3C(C)=CC=CC=3N)C=CC=2)(=O)=O)C=1)=N)(C)(C)C.NCCC#N.[N:81]([Si](C)(C)C)=[N+:82]=[N-:83].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:41])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:39][CH3:40])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH:31][C:32]([NH:34][CH2:35][CH2:36][C:37]3[N:81]=[N:82][NH:83][N:38]=3)=[O:33])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCC#N)c1
Agent: CCCC[Sn](=O)CCCC
Agent: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Agent: N#CCCN
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCc2nn[nH]n2)c1
Temperature: 80 °C
Yield: 41.8 %

Procedure:
A mixture of [(4-{2′-[3-(2-cyano-ethyl)-ureido]-6′-methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert-butyl ester (31 mg, 51 μmol), as prepared from {[4-(2′-amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester and 3-aminopropionitrile according to the procedure of step e of Example 179, azidotrimethylsilane (40 μL, 0.30 mmol), dibutyltin oxide (3.5 mg, 10 μmol), and toluene (1.5 mL) was heated at 70° C. for 16 h and 80° C. for 4 h. The mixture was concentrated and purified by flash chromatography on silica gel, eluting with EtOAc/DCM (50, 100%) followed by MeOH/DCM (5, 10%) to give the title compound (14 mg, 42% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[CH:18]=[C:19]([CH3:23])[N:20]=[N:21][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:18]=[C:19]([CH3:23])[N:20]=[N:21][CH:22]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Cc1cc(Cl)cnn1
Product: Cc1cc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)cnn1

Procedure:
The title compound, MS: m/e=309.2 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 5-chloro-3-methyl-pyridazine.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=O)[CH:16]=2)[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]([CH3:25])=[CH:22][C:23]#[N:24]>C(O)(=O)C>[CH2:1]([S:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:16]([CH3:15])=[C:17]3[C:9]#[N:10])[CH:16]=2)[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2[nH]nc(SCc3ccccc3)c2c1
Reactant: CC(N)=CC#N
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(SCc4ccccc4)c3c2)C(C#N)=C(C)N1

Procedure:
The crude product obtained in Example 8A and 29.6 mg (0.361 mmol) 3-aminobut-2-enenitrile in acetic acid (4 ml) were heated to 110° C. for 1 h. After cooling, the reaction mixture was directly purified by preparative RP-HPLC (acetonitrile/water+0.05% TFA gradient) yielding 30 mg (46% of th.) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.C1COCC1.[Cl:21]N1C(=O)CCC1=O>O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[C:11]([Cl:21])[C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(O)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a mixture of methyl((3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate (10.4 g) and THF (20 mL) was added N-chlorosuccinimide (6.67 g). The mixture was stirred at room temperature overnight. The mixture was poured into water 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 (8.8 g).
Reaction SMILES: [I:1]Cl.C[Sn](C)(C)[C:5]1[CH:6]=[C:7]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:8]=[N:9][CH:10]=1.[OH-].[Na+]>ClCCl>[I:1][C:5]1[CH:6]=[C:7]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:8]=[N:9][CH:10]=1
Reactant: ClI
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc([Sn](C)(C)C)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(I)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of Iodomono chloride (588 mg, 3.6 mmol) and anhydrous dichloromethane (10 ml) was added to a mixture of 1-(5-trimethylstannyl-3-pyridyl)-4-tert-butoxycarbonyl-homopiperazine (1.45 g, 3.3 mmol) and dichloromethane (30 ml). The mixture was stirred at room temperature for 1 hours. Aqueous sodium hydroxide (25 ml, 1 M) was added. The organic phase was separated. The aqueous phase was extracted with dichloromethane (25 ml). The combined organic phases was purified by chromatography on silica gel with dichloromethane and methanol (19:1) The title compound was isolated as an oil. Yield 0.80 g, 60%.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[CH:9]=[CH:10][C:11]2[O:20][CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([C:21]4[N:22]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])[N:23]=[CH:24][N:25]=4)[S:14][C:13]=3[C:12]=2[N:34]=1.[C:35](Cl)(=[O:37])[CH3:36].CCN(C(C)C)C(C)C.O>C1COCC1>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:22]1[C:21]([C:15]2[S:14][C:13]3[C:12]4[N:34]=[C:8]([N:2]5[CH2:3][CH:4]6[CH2:7][CH:1]5[CH2:6][N:5]6[C:35](=[O:37])[CH3:36])[CH:9]=[CH:10][C:11]=4[O:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)=[N:25][CH:24]=[N:23]1
Reactant: CC(=O)Cl
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(N4CC5CC4CN5)ccc2OCC3)c(F)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CC2CC1CN2c1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
Compound 310 (479 mg, 1.0 mmol), Acetyl chloride (100 mg, 1.2 mmol), DIPEA (260 mg, 2.0 mmol) was dissolved in THF (10 mL). The reaction mixture was stirred at r.t. for 1 hour. LC-MS indicated the reaction was completed. To the reaction mixture was added 20 mL of water, the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness. The crude was purified by pre-HPLC to afford 311 (78.1 mg, yield: 15%). 1HNMR (DMSO-d6, 400 MHz): δ8.27 (s, 1H), 7.91-7.90 (m, 1H), 7.74 (s, 1H), 7.43-7.39 (m, 1H), 7.23-7.20 (m, 2H), 6.48 (t, J=4.4 Hz, 1H), 4.77 (s, 2H), 3.53 (s, 2H), 3.53-3.32 (m, 4H), 3.19 (s, 2H), 1.96 (s, 3H), 1.23 (s, 2H). ESI-MS: m/z=521 [M+H+]
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:33]1[O:43][C:42]2[CH:41]=[CH:40][C:37]([CH2:38]I)=[CH:36][C:35]=2[O:34]1.C(O)(=O)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C.O.CN1CCCN(C)C1=O>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:38][C:37]2[CH:40]=[CH:41][C:42]3[O:43][CH2:33][O:34][C:35]=3[CH:36]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Reactant: ICc1ccc2c(c1)OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: CCC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc3c(c2)OCO3)C(=O)O1
Temperature: -75 °C
Reaction time: 0.33 h

Procedure:
Under an N2 atmosphere, a solution of 500 mg of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Example 2b)] in 2 ml of abs. THF and 0.33 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU) is cooled down to -75° C. and treated, at an internal temperature of below -70° C., with 3.21 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF (Aldrich, Steinheim, FRG), and this mixture is then stirred at -75° C. for 20 min. 429 mg of 3,4-methylenedioxybenzyl iodide in 1 ml of abs. THF are added dropwise to the reaction solution within the space of 10 min using a syringe, during which period the internal temperature is not allowed to exceed -70° C., and this mixture is then thoroughly stirred at -75° C. for 1 h. 0.611 ml of propionic acid are then added to the clear solution, at from -75° C. to -70° C., using a syringe, and this is followed by 0.611 ml of water. During this procedure, the temperature rises to -30° C. After that, the reaction mixture is diluted with 35 ml of ethyl acetate, and the whole is stirred up with 10 ml of 10% citric acid solution for 5 min in the cold (ice/water cooling). The aqueous phase is separated off and the organic phase is washed, in succession, with saline, sat. sodium bicarbonate solution, and once again with saline. The combined aqueous phases are reextracted 2 times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The title compound is obtained as a brownish oil. Purification is effected by chromatography on silica gel (eluent D). TLC Rf (D)=0.38; FAB-MS (M+H)+ =440.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17])=[O:10].C(=O)(O)[O-].[Na+].[Br:23][CH2:24][C:25](Br)=[O:26]>C(Cl)Cl>[Br:23][CH2:24][C:25]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17])=[O:26]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(F)cc1C(=O)c1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc(F)cc1C(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.95 g (10 mmol) of (2-amino-5-fluorophenyl)(2-bromophenyl)methanone in 50 mL of methylene chloride was layered with 50 mL of saturated sodium bicarbonate solution. Bromoacetyl bromide, 1.35 mL (15 mmol) was added to the organic layer and the mixture was stirred at room temperature for 15 minutes. The organic layer was separated, dried and evaporated. The residue was crystallized from ether/hexane to yield 3.85 g of product having the above formula with m.p. 110°-114° C. For analysis, a sample of product was recrystallized from ether/hexane to leave colorless crystals with m.p. 113°-115° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22]2.O>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH:23]=[CH:22]2
Reactant: COc1ccc2cc(O)ccc2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cc(Oc3ccc([N+](=O)[O-])cc3)ccc2c1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 6-methoxy-2-naphthol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 mL), extracted with EtOAc (2×50 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(6-methoxy-naphthalen-2-yloxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][CH2:43][N:42]([CH:45]6[CH2:48][O:47][CH2:46]6)[CH2:41][C@@H:40]5[CH2:49][CH3:50])=[CH:35][N:34]=4)[C:29](=[O:51])[N:28]([CH3:52])[CH:27]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][CH2:43][N:42]([CH:45]6[CH2:46][O:47][CH2:48]6)[CH2:41][C@@H:40]5[CH2:49][CH3:50])=[CH:35][N:34]=4)[C:29](=[O:51])[N:28]([CH3:52])[CH:27]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nc1
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To a solution of 111g (100 mg, 0.14 mmol) at 0° C. in methanol (5 mL) was added sodium borohydride (16.0 mg, 0.42 mmol). The mixture was stirred for 60 minutes. It was then quenched with water (1.0 mL) and concentrated. The residue was purified by reverse-phase prep-HPLC to afford 111 (32 mg, 32%). MS: [M+H]+ 712.3. 1H NMR (500 MHz, CDCl3) δ 8.57 (d, J=2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.58 (s, 2H), 7.41 (d, J=2.0 Hz, 1H), 7.31-7.28 (m, 2H), 7.12 (dd, J=2.5, 8.5 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 4.73-4.70 (m, 4H), 4.37 (s, 2H), 3.74-3.72 (m, 1H), 3.71 (s, 3H), 3.56-3.54 (m, 1H), 3.34-3.32 (m, 1H), 3.15-3.13 (m, 2H), 2.58-2.36 (m, 4H), 1.45 (s, 9H), 1.44-1.43 (m, 2H), 0.83 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.[C:32](=S)=[S:33].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:20]1([CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH2:10][N:9]3[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]=[C:32]3[SH:33])[CH2:18][CH2:17]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: S=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Sc1nc2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 4.37 parts of N-(2-aminophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine hydrochloride, 38 parts of carbon disulfide, 2 parts of sodium carbonate and 40 parts of ethanol is stirred and refluxed for 20 hours. The reaction mixture is evaporated and water is added to the residue. The precipitated product is filtered off, washed with water and dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1H-benzimidazole-2-thiol; mp 181.8° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C:5]([CH3:37])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4C)[CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])[CH3:2]>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:38])[C:5]([CH3:37])([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(Oc4ccccc4C)c3)oc2C)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(Oc4ccccc4)c3)oc2C)cc1

Procedure:
2-Methyl-2-(4-{2-[5-methyl-2-(3-o-tolyloxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester Rf=0.45 in 1:4 EtOAc:hexanes; MS (EI) 554.1 (M+K)+, 516.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[NH:8][CH2:7][CH:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:5]2.[H][H]>[Pd].C(O)C>[NH2:12][C:10]1[CH:11]=[CH:2][CH:3]=[C:4]2[C:9]=1[NH:8][CH2:7][CH:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:5]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1CNc2c(cc(Br)cc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CNc2c(N)cccc2C1
Yield: 103.3 %

Procedure:
A mixture of t-butyl (6-bromo-1,2,3,4-tetrahydro-8-nitro-3-quinolinyl)-carbamate (3.72 g, 0.01 mol), absolute ethanol (150 mL) and 10% palladium on carbon (0.60 g) was hydrogenated (50 lb hydrogen pressure) for 18 hours. The mixture was filtered through celite and the solvent removed. The residual foam was partitioned between ethyl acetate and 1 N sodium hydroxide, and the ethyl acetate phase was evaporated under reduced pressure to give 2.72 g of t-butyl (8-amino-1,2,3,4-tetrahydro-3-quinolyl)carbamate (compound XXXII) as an oil.
Reaction SMILES: [C:1]1([C@@H:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:14]([NH:13][C@H:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:12])(=[O:16])[CH3:15]
Reactant: C[C@H](N)c1cccc2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N[C@@H](C)c1cccc2ccccc12
Temperature: 38 °C
Reaction time: 12 h
Yield: 59479.9 %

Procedure:
5 g of (S)-(-)-α-(1-naphthyl)ethylamine (manufactured by Hydras Kagaku) was dissolved in 20 ml of pyridine, and 5.07 mg of acetic anhydride was added thereto under cooling with ice. The mixture was stirred at 38° C. for 12 hours. The reaction solution was diluted with 500 ml of chloroform, and the organic layer was sequentially washed with a dilute hydrochloric acid aqueous solution, a dilute sodium hydroxide aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The reaction mixture thus obtained was recrystallized from dried ethanol to obtain 6.3 g of N-acetyl-(S)-α-(1-naphthyl)ethylamine. This substance is a known compound, and the measured values of various physical properties agreed to the values disclosed in literatures.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[O:12][CH2:11]1.[OH-].[K+]>CO>[O:12]1[C:13]2([CH2:18][CH2:17][C:16]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[CH:15][CH2:14]2)[O:20][CH2:10][CH2:11]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Yield: 89.1 %

Procedure:
Indole (4.69, 40 mmol), 1,4-cyclohexanedione monoethylene ketal (6.3 g, 40 mmol) and potassium hydroxide (13.2 g, 200 mmol) were heated to reflux in 70 ml methanol for 6 hours. The reaction was cooled and the product was isolated by filtration and washed with water to give 9.1 g (89%) of product.