Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4](I)=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(O)(C)C.C(N(CC)CC)C.[H][H]>O>[Br:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1nc(Br)[nH]c1I
Reactant: [H][H]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=[N+]([O-])c1c[nH]c(Br)n1

Procedure:
A mixture consisting of 2-bromo-5-iodo-4-nitroimidazole (2.43 g, 7.64 mmol), isopropyl alcohol (12.2 ml), water (2.4 ml), triethylamine (2.32 g, 22.9 mmol), and 5% Pd-alumina (12.2 mg) was stirred while applying pressure (3 to 4 atmospheres) in a hydrogen atmosphere at 60° C. for 3 hours. The filtrate was concentrated and exsiccated under reduced pressure, and the resultant product was then dissolved in water (10 ml). The thus obtained solution was treated with activated carbon (243 mg) (which was stirred at room temperature for 1 hour). The filtrate was stirred under cooling on ice, and 35% concentrated hydrochloric acid (0.7 ml) was added thereto such that the pH of the solution became 2. The thus obtained solution was further stirred under cooling on ice for 1 hour. Thereafter, the precipitated crystals were collected by filtration and then dried at 50° C. for 16 hours.
Reaction SMILES: O[C:2]1([C:18]2[C:22]([CH3:23])=[C:21]([Br:24])[S:20][C:19]=2[F:25])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C([SiH](CC)CC)C>[Br:24][C:21]1[S:20][C:19]([F:25])=[C:18]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]2)[C:22]=1[CH3:23]
Reactant: Cc1c(Br)sc(F)c1C1(O)CCN(C(=O)OCc2ccccc2)CC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)sc(F)c1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
To an ice-cooled, rapidly stirred slurry of 4-hydroxy-4-(5-bromo-2-fluoro-4-methylthiophenyl)-N-Cbz-piperidine (7.82 g) in triethylsilane (19.7 g) was slowly added tri-fluoroacetic acid (18.6 g). When addition was complete the mixture was warmed to room temperature and stirred overnight (18 h). At the end of this period the mixture was poured into 100 mL saturated NaHCO3 and extracted with DCM. Extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give an oil. The product was purified by chromatography on silica (7:3, hexane:EtOAc) to give 5.18 g of an oil; MS m/z 438 (M+); 1H NMR (CDCl3) δ 7.45-7.30 (m), 7.25 (d), 6.80 (d), 5.15 (s), 4.50-4.20 (m), 3.11-2.80 (m), 1.90-1.48 (m).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)([CH3:20])[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH:29][NH:30][C:31](=N)[CH:32]([CH3:34])[CH3:33]>>[CH:32]([C:31]1[N:28]=[C:27]([N:24]2[CH2:25][CH2:26][CH:21]([C@@:18]3([CH3:20])[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:22][CH2:23]2)[O:29][N:30]=1)([CH3:34])[CH3:33]
Reactant: C[C@@]1(C2CCN(C#N)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: CC(C)C(=N)NO
Product: CC(C)c1noc(N2CCC([C@]3(C)Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from (S)-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile (Intermediate 42; the configuration of the stereocenter is arbitrarily assigned) and N-hydroxy-isobutyramidine following a procedure analogous to that described in Example 2. LC (method 4): tR=0.97 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:15]([OH:17])=O)[C@H:9]([C:11]([F:14])([F:13])[F:12])[CH3:10])=[O:6])[CH:2]=[CH2:3].[NH2:18][C:19]1[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:22][C:23]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.N1C=CC=CC=1>[CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:15]([NH:18][C:19]1[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:22][C:23]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]1)=[O:17])[C@H:9]([C:11]([F:12])([F:13])[F:14])[CH3:10])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N[C@H](C(=O)O)[C@@H](C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(N)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C=CCOC(=O)N[C@H](C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2)ccc1Cl)[C@@H](C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
398.5 mg (1.56 mmol) of (3R)—N-[(allyloxy)carbonyl]-4,4,4-trifluorovaline (diastereomer mixture) and 400 mg (1.42 mmol) of tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate were dissolved in a mixture of 4.7 ml of DMF and 1.6 ml of pyridine, and 647.8 mg (1.70 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight. A further 400 mg (1.42 mmol) of tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate and 647.8 mg (1.70 mmol) of HATU were added, and the reaction mixture was stirred at 50° C. for another 4 h. After dilution with ethyl acetate, the mixture was washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water). This gave 453 mg of the target product (55.9% of theory, diastereomer ratio >8:1).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:21]([CH3:34])=[C:22]([CH3:33])[C:23]4[O:27][C:26]([CH2:29][OH:30])([CH3:28])[CH2:25][C:24]=4[C:31]=3[CH3:32])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>O.C(OCC)(=O)C>[CH3:42][S:43]([O:30][CH2:29][C:26]1([CH3:28])[CH2:25][C:24]2[C:31]([CH3:32])=[C:20]([N:17]3[CH2:16][CH2:15][N:14]([C:11]4[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=4)[CH2:19][CH2:18]3)[C:21]([CH3:34])=[C:22]([CH3:33])[C:23]=2[O:27]1)(=[O:45])=[O:44]
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CO)O4)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(COS(C)(=O)=O)O4)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
To a solution of THF (2.0 mL) containing {5-[4-(4-Methoxyphenyl)piperazin-1-yl]-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl}methanol (200 mg, 0.504 mmol) synthesized in Example 97, triethylamine (102 mg, 1.01 mmol) and methanesulfonyl chloride (87 mg, 0.756 mmol) were serially added under ice-cooling condition, and the mixture was warmed to room temperature and stirred for 15 hours. The reaction solution was diluted with water, and extraction was performed using ethyl acetate. The extract was washed with saturated saline and dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5-75:25) to give 220 mg of the title compound (yield: 92%). An amorphous solid.
Reaction SMILES: [ClH:1].FC1C=CC(F)=CC=1[N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.Br[C:16]1[CH:17]=[C:18]([F:26])[CH:19]=[CH:20][C:21]=1[O:22][CH:23]([F:25])[F:24]>>[ClH:1].[F:24][CH:23]([F:25])[O:22][C:21]1[CH:20]=[CH:19][C:18]([F:26])=[CH:17][C:16]=1[C@H:11]1[CH2:12][CH2:13][CH2:14][NH:10]1
Reactant: Fc1ccc(F)c(N2CCCC2)c1
Reactant: Fc1ccc(OC(F)F)c(Br)c1
Agent: Cl
Product: Fc1ccc(OC(F)F)c([C@H]2CCCN2)c1

Procedure:
This compound was prepared by the method substantially similar to the preparation of 2,5-difluorophenyl pyrrolidine hydrochloride as mentioned in Example 1 step 5 using 3-bromo-4-(difluoromethoxy)-1-fluorobenzene (J. Med. Chem. 2003, 46, 1016-1030).
Reaction SMILES: C([Li])CCC.[N:6]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=2)[CH2:9][CH2:8][CH2:7]1.CN(C)[CH:19]=[O:20]>O1CCCC1>[N:6]1([C:10]2[N:11]=[C:12]([CH:19]=[O:20])[CH:13]=[CH:14][CH:15]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: Brc1cccc(N2CCC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(N2CCC2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
A solution of n-butyllithium in hexanes (0.3 g, 4.69 mmol) was added dropwise to a solution of 2-(azetidin-1-yl)-6-bromopyridine (0.5 g, 2.34 mmol) in dry tetrahydrofuran (20 mL) at −78° C. After stirring for 30 min at −78° C., N,N-dimethylformamide (0.34 g, 4.69 mmol) was added. The reaction mixture was stirred for 3 h at −78° C., then the reaction mixture was quenched with an aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (60-120 mesh silica; 4-5% ethyl acetate in petroleum ether, twice) to afford 6-(azetidin-1-yl)picolinaldehyde (0.2 g, 43%). MS (ES+) (M+H) 163.1380; LCMS retention time: 5.59 minutes (Method X).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.O=[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH2:32])=[O:31].C(O)(=O)C.C([O-])(=O)C.[Na+]>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:25](/[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)\[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH2:32])=[O:31])=[CH:22][CH:23]=1
Reactant: NC(=O)CCCCC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCC(N)=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (600 mg), 6-oxo-6-phenylhexanamide (396 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and ethanol (20 ml) was heated to reflux for 18 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain crystals from an ethyl acetate-hexane (3:1, v/v)-eluted fraction. The crystals were recrystallized from ethyl acetate-hexane to obtain E-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanamide (651 mg, yield 68%) as colorless crystals. m.p. 95-96° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[CH:5][CH:4]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[CH:5][CH:4]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(CO)n1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(COS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
tert-Butyl (2R)-2-({[6-(hydroxymethyl)pyridin-2-yl]oxy}methyl)pyrrolidine-1-carboxylate (430 mg, 1.4 mmol) was dissolved in DCM (15 mL) and MsCl (240 mg, 2.1 mmol) was added. The reaction mixture was cooled to 0° C. and DIPEA (0.72 mL, 4.1 mmol) were added. The reaction mixture was stirred 2 h at ambient temperature and water was added. The organic phase was separated and evaporated. The residue was purified by flash chromatography using a gradient of EtOAc/heptane to give the title compound as a clear oil. Yield: 420 mg (78%). 1H NMR (399.961 MHz, CDCl3) δ 7.61 (t, J=8.2 Hz, 1H), 7.01 (d, J=6.6 Hz, 1H), 6.72 (d, J=8.5 Hz, 1H), 5.20 (s, 2H), 4.49-4.30 (m, 1H), 4.27-4.06 (m, 2H), 3.50-3.27 (m, 2H), 3.07 (s, 3H), 2.04-1.90 (m, 3H), 1.90-1.81 (m, 1H), 1.46 (s, 9H). MS (ESI+) 387.2 (M+1H+).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CC(N(C)C)=O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cccc2c(Br)cccc12
Reactant: Nc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc2c(Nc3ccc(Cl)cc3)cccc12
Temperature: 140 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
1-bromo-5-nitronaphthalene (131 mg, 0.52 mmol) was dissolved in DMA (5 mL), and added with 4-chloroaniline (60 mg, 0.47 mmol), Xantphos (27 mg, 0.047 mmol), Pd2(dba)3 (17.2 mg, 0.019 mmol) and CsCO3 (306 mg, 0.94 mmol) at room temperature. The reaction solution was sealed and stirred for about 3 hours under microwave conditions at 140° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound purified using silica gel chromatography (ethyl acetate:hexane=1:5 (v/v)) to obtain the title compound (92 mg, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][CH2:8][N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.CO.C(OCC)(=O)C.C([O-])=O.[NH4+]>C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:28][CH:29]=1
Reactant: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1ccc(N)cc1

Procedure:
To a clear solution of methyl 3-[(4-methoxyphenethyl)-(4-nitrobenzensulfonyl)-amino]-propionate in 5:1 methanol/ethyl acetate (4.2 mL/mmol) is added by portion palladium (10%) in charcoal solid (10% w/w), followed by ammonium formate (4 eq.). The resulting mixture is refluxed for 6 hours and filtered through a pad of celite. Filtrate is concentrated and partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated to give methyl 3-[(4-methoxyphenethyl)-(4-aminobenzenesulfonyl)-amino]-propionate as a brown oily product in quantitative yield.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)=O)(C)(C)C.[CH2:20](N1CCCC1C1C=CC(Br)=CC=1)[CH:21]=C>>[CH2:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1)[CH:20]=[CH2:21]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(N)cc1
Reactant: C=CCN1CCCC1c1ccc(Br)cc1
Product: C=CCN1CCCC1c1ccc(N)cc1
Yield: 87 %

Procedure:
Using the same procedure described for the preparation of 2-(4-Amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, the title compound is prepared from 1-Allyl-2-(4-bromo-phenyl)-pyrrolidine (470 mg, 1.77 mmol) in 87% yield.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:8]([C:10](OC)=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCc1nc(CO)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 89.8 %

Procedure:
Following a procedure similar to that described in Example 35(b), 0.51 g of dimethyl 2-butyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-4,5-dicarboxylate [prepared as described in step (a) above] was reduced using 0.99 ml of a 1.5M solution of diisobutylaluminum hydride in toluene, to give 0.44 g of the title compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:19][CH3:20])=[C:6]([C:11]2[O:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][CH:12]=2)[CH:7]=[C:8]([CH3:10])[CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:5]([O:19][CH3:20])=[C:6]([C:11]2[O:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][CH:12]=2)[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: COc1c(-c2ccc(C(=O)O)o2)cc(C)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1c(N)cc(C)cc1-c1ccc(C(=O)O)o1
Yield: 97.3 %

Procedure:
5-(3-Nitro-2-methoxy-5-methyl-phenyl)-furan-2-carboxylic acid 46a (410 mg, 1.48 mmol) was dissolved in 28 mL of ethyl acetate followed by addition of 61 mg of palladium on carbon and ammonium formate (658 mg, 10.44 mmol). Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered to remove palladium on carbon. The filtrate was concentrated under reduced pressure and dried to obtain the title compound 5-(3-amino-2-methoxy-5-methyl-phenyl)-furan-2-carboxylic acid 46b (356 mg, yield 97.3%) as a white solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:41]=[CH:40][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[C@@H:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]([O:33]C(=O)C(C)(C)C)[CH:27]=[CH:26][C:25]=3[CH2:24]2)=[CH:7][CH:6]=1)(O)=O.[CH3:42][C:43]1([CH3:49])[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]1>>[CH3:42][C:43]1([CH3:49])[CH2:48][CH2:47][CH2:46][N:45]([CH2:1][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=3[C@@H:23]3[CH2:32][CH2:31][C:30]4[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26][C:25]=4[CH2:24]3)=[CH:40][CH:41]=2)[CH2:44]1
Reactant: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Reactant: CC1(C)CCCNC1
Product: COc1cc(NCCCc2ccc(CCN3CCCC(C)(C)C3)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 22.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 3,3-dimethylpiperidine (20 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (4.3 mg) was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6]O[C:4]([C:8]([OH:10])=[O:9])=[C:3]1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH2:23]>C(O)C>[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][N:23]1[CH:6]=[CH:7][C:2](=[O:1])[C:3]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]1[C:8]([OH:10])=[O:9]
Reactant: COC(CN)OC
Reactant: O=C(O)c1occc(=O)c1OCc1ccccc1
Solvent: CCO
Product: COC(Cn1ccc(=O)c(OCc2ccccc2)c1C(=O)O)OC
Reaction time: 18 h

Procedure:
To a flask (1 L) charged with 500 mL of anhydrous ethanol was added 49.2 g (0.2 mol) of 4-oxo-3-[(phenylmethyl)oxy]-4H-pyran-2-carboxylic acid 5. The suspension was slowly heated to 55-60° C. before addition of 2-amino-acetaldehyde-dimethylacetal (84.1 g, 0.8 mole). The reaction was then brought up to 65° C. and further stirred for 18 hours. The solvent was removed under reduced pressure to produce 1-[2,2-Bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid 22 (crude) as brown oil, which was used for the next step directly.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:12]([CH3:13])=[C:11]([CH3:14])[CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([CH3:17])[CH:8]2OC.CC1C=CC(S(O)(=O)=O)=CC=1.BrCCC1C(C)=C(C)C=C2C=1C=C(C)C2>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][C:4]1[C:12]([CH3:13])=[C:11]([CH3:14])[CH:10]=[C:9]2[C:5]=1[CH2:6][C:7]([CH3:17])=[CH:8]2
Reactant: COC1c2cc(C)c(C)c(CCBr)c2CC1C
Agent: CC1=Cc2c(cc(C)c(C)c2CCBr)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=Cc2cc(C)c(C)c(CCBr)c2C1

Procedure:
To a hot (110° C.) solution of 6.28 g (21.13 mmol) of 4-(2-bromoethyl)-1-methoxy-2,5,6-trimethylindane in 75 ml of toluene 0.4 g of TsOH*H2O was added. This mixture was refluxed with Dean-Stark trap for 10 min and then passed through the layer of Silica Gel 60 (40-63 um, d 80 mm, l 50 mm). The Silica Gel layer was additionally washed by 300 ml of toluene. The combined organic extract was evaporated to dryness. The product was isolated by flash chromatography using a short column with Silica Gel 60 (40-63 um, d 80 mm, l 50 mm; eluent: hexanes). Yield 5.38 g (96%) of 4-(2-bromoethyl)-2,5,6-trimethyl-1H-indene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[NH2:16][OH:17].Cl.CC(O[Na])=O.C([O-])(O)=O.[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:16][OH:17])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Agent: CC(=O)O[Na]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Product: COC(=O)CCC(=NO)c1ccc(Br)cc1
Yield: 62.7 %

Procedure:
To a solution of methyl 4-(4-bromophenyl)-4-oxobutanoate (8.0 g, 29 mmol) and NH2OH.HCl (4.8 g, 69 mmol) in MeOH (60 mL) was added a solution of CH3COONa (6.0 g, 73 mmol) in H2O (30 mL) at room temperature. The reaction mixture was heated at reflux for 1 h. The mixture was neutralized with saturated NaHCO3 solution and was extracted with ethyl acetate (50 mL×3). The combined organics were washed with brine, dried over anhydrous Na2SO4, and purified by chromatography on silica gel (3% ethyl acetate in petroleum ether) to afford methyl 4-(4-bromophenyl)-4-(hydroxyimino)butanoate (5.2 g, 62%). 1H NMR (CDCl3, 400 MHz) δ 7.52-7.49 (m, 4H), 3.66 (s, 3H), 3.08 (t, J=8.0, 2H), 2.61 (t, J=8.0, 2H).