Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][S:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:10]=1[CH3:28])C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH2:21]([S:20][CH2:19][C:11]1[NH:12][C:13]2[C:18]([C:9](=[O:8])[C:10]=1[CH3:28])=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCSCc1nc2ccccc2c(OCc2ccccc2)c1C
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCSCc1[nH]c2ccccc2c(=O)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a solution of 4-(benzyloxy)-2-[(heptylsulfanyl)methyl]-3-methylquinoline (150 mg) in trifluoroacetic acid (5 mL) was added thioanisole (150 mg), followed by stirring at room temperature for 16 hours. The reaction mixture was added dropwise to an ice-cold aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 2-[(heptylsulfanyl)methyl]-3-methylquinolin-4(1H)-one (110 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=O.S(O)(O)(=O)=O.[CH3:18][NH:19][NH2:20].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[N:19]([CH3:18])[N:20]=[CH:7][CH:6]=2)[CH:3]=1
Reactant: CNN
Reactant: O=c1ccoc2ccc(Cl)cc12
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(Cl)ccc1O
Temperature: 25 °C

Procedure:
To a suspension of 6-chlorochromone (2.00 g, 0.011 mol) in ethanol (35 mL) was added methylhydrazine sulfate (1.85 g, 0.013 mol) and triethylamine (2.0 mL, 0.014 mol) and the mixture was heated at reflux for 18 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the resulting residue purified by silica gel chromatography eluting with 0 to 100% EtOAc in hexane to yield two regioisomeric products in a 1:4 ratio, the title compound being the minor regiosiomer.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].[CH3:17][C:18]1([CH3:27])[CH:23]2[CH2:24][CH:19]1[C:20](=[O:26])[CH2:21][C:22]2=[O:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH3:9])=[C:2]([CH:21]3[C:20](=[O:26])[CH:19]4[CH2:24][CH:23]([C:18]4([CH3:17])[CH3:27])[C:22]3=[O:25])[CH:3]=2)=[CH:11][CH:12]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1Br
Reactant: CC1(C)C2CC1C(=O)CC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C2CC(C1=O)C2(C)C
Temperature: 160 °C

Procedure:
3-Bromo-4′-chloro-4-ethylbiphenyl (0.200 g, 0.68 mmol) is added to a mixture of 6,6-dimethylbicyclo[3.1.1]heptane-2,4-dione (0.124 g, 0.81 mmol), prepared by the method of W. Childers et al., US2006/0004108, powdered potassium phosphate (0.316 g, 1.49 mmol), palladium (II) acetate (0.008 g, 0.034 mmol) and (2-dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.024 g, 0.051 mmol) in degassed 1,2-dimethoxyethane (2 ml) and the mixture is stirred and heated to 160° C. for 1 hour under microwave irradiation. The mixture is cooled to room temperature, diluted with ethyl acetate and washed with 2 M aqueous hydrochloric acid. The organic phase is washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is taken up in N,N-dimethylformamide (2 ml) and purified by preparative reverse-phase HPLC to give 3-(4′-chloro-4-ethylbiphen-3-yl)-6,6-dimethylbicyclo[3.1.1]heptane-2,4-dione.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5].[NH4+].[Cl-]>C1COCC1.[Zn]>[NH2:11][C:10]1[C:2]([Cl:1])=[C:3]([C:7]([Cl:14])=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: Nc1ccc(Cl)c(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.5 %

Procedure:
2,6-Dichloro-3-nitrobenzoic acid (2.13 g, 9.03 mmol) was dissolved in 2:1 THF:saturated aqueous NH4Cl and cooled to 0° C. The mixture was treated with zinc (11.8 g, 181 mmol). The reaction mixture was allowed to warm to ambient temperature and stir for 24 hours. The reaction mixture was filtered through GF/F paper while rinsing with THF. The mixture was acidified to a pH of 1 using 1.0M HCl and extracted with 15% 2-propanol:DCM (3×). The extracts were washed with water and brine, dried over sodium sulfate and concentrated to afford 3-amino-2,6-dichlorobenzoic acid (1.40 g, 6.82 mmol, 75.5% yield). MS (APCI-neg) m/z=203.6 (M−H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[CH:9][C:10]=2[F:11])[CH2:3][CH2:2]1.[NH:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:14]([C:16](O)=[O:17])[CH3:15].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C2=CC=CC=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:1]1([NH:4][C:5]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:16](=[O:17])[C@@H:14]([NH:13][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH3:15])[CH2:3][CH2:2]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccc(F)c1NC1CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(F)c1NC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N1-cyclopropyl-6-fluorobenzene-1,2-diamine (392.7 mg, 2.363 mmol) in DMF (3 mL) was added Boc-L-Ala-OH (447 mg, 2.363 mmol), 1,1′-dimethyltriethylamine (822 μL, 4.73 mmol) and (1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (1.23 mg, 2.36 mmol) and the resulting mixture was stirred at rt for 4 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using EtOAc:DCM (1:1) as eluent to give (S)-tert-butyl 1-(2-(cyclopropylamino)-3-fluorophenylamino)-1-oxopropan-2-ylcarbamate: LC-MS (ESI) m/z 338.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,5-dichloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([O:14]C)[C:5]2[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[CH:3]=1.ClC1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:1][C:2]1[CH:13]=[C:12]([OH:14])[C:5]2[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(Cl)cc2oc(C(C)=O)cc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CC(=O)c1cc2c(O)cc(Cl)cc2o1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a stirred solution of 1-(6-chloro-4-methoxybenzofuran-2-yl)ethanone (Example 37C, 1.43 g, 6.37 mmol) in chlorobenzene (15 mL, 148 mmol) was added aluminum chloride (3.40 g, 25.5 mmol) in portions over a period of 10 minutes. The reaction vessel was then sealed and heated at 100° C. for 40 minutes, then cool to r.t. and poured onto crushed ice (rinsed stirring bar with EtOAc). This was stirred for 30 minutes, then extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The residue was purified by ISCO using hexanes/EtOAc as eluent. Fractions containing the desired product were concentrated to give the title material (1.18 g, 5.60 mmol, 88% yield) as a light brown solid. LC (Method A): 1.783 min. LCMS (APCI) calcd for C10H8ClO3 [M+H]+ m/z 211.02, found 211.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 11.01 (s, 1H), 7.89 (s, 1H), 6.72 (s, 1H), 2.52 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][CH:7]([C:9]1[N:14]=[N:13][C:12]([NH:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)=[N:11][CH:10]=1)[CH3:8])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[Br:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]1[N:14]2[C:9]([CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[N:13]2)=[C:7]([CH3:8])[N:6]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3Br)nn2)cc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4Br)n3n2)cc(OC)c1OC
Yield: 1.6 %

Procedure:
In a similar manner as described for Example 1, 2-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 12) (0.45 g, 0.92 mmol) in 1,2-dichloroethane (20 mL) and phosphorus oxychloride (0.69 mL, 7.4 mmol) gave 7-(2-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.0069 g) as a yellow solid. 1H NMR (CDCl3): δ8.85 (s, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.58 (dd, J=7.6, 1.4 Hz, 1H), 7.44 (dd, J=7.7, 7.3 Hz, 1H), 7.35 (ddd, J=7.9, 7.7, 1.4 Hz, 1H), 6.99 (s, 1H), 6.83 (s, 2H), 3.78 (s, 3H), 3.62 (s, 6H), 2.64 (s, 3H). MS m/z 470, 472 (M+1, M+3).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].O.[C:25](O)(=[O:27])[CH3:26]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:25](=[O:27])[CH3:26])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Reactant: CC(=O)O
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C(C)=O)CC3)cc21
Yield: 97 %

Procedure:
1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid 3.2 g was dissolved in 20 ml of glacial acetic acid, 2.0 g of anhydrous acetic acid was added thereto and the mixture was heated at 90°-100° C. for 2 hours with stirring. After cooling, 50 ml of water was added thereto. The precipitated crystals were collected by filtration, washed and dried. The crystals were recrystallized from dimethylformamide to obtain 3.5 g (97%) of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-acetyl-1-piperazinyl)quinoline-3-carboxylic acid as colorless needles.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[C:19]([F:31])[CH:18]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[CH2:1]([NH:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([F:31])[CH:18]=2)=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(NCc2ccccc2)ncc(-c2ccc(OCc3ccccc3)c(F)c2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(NCc2ccccc2)ncc(-c2ccc(O)c(F)c2)c1=O

Procedure:
A solution of 2-(benzylamino)-5-(4-(benzyloxy)-3-fluorophenyl)-3-methylpyrimidin-4(3H)-one (0.145 g, 0.349 mmol) in TFA (4 mL) was stirred at 40° C. for 5 hours. The reaction was concentrated to dryness and then dried under vacuum to yield a crude residue that was purified by flash column chromatography, eluting with 20:1 CH2Cl2/MeOH. The product was obtained (105 mg; 93%) as a white foam solid. 1H NMR (400 MHz, DMSO-d6) δ 9.74 (br s, 1H), 7.93 (br s, 1H), 7.84 (s, 1H), 7.45 (m, 1H), 7.38-7.29 (m, 4H), 7.27-7.20 (m, 2H), 6.89 (t, 1H), 4.62 (d, 2H), 3.41 (s, 3H). LRMS (APCI pos) m/e 326 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:21][CH:22]=2)=[CH:11][C:10]=1[CH2:29][OH:30])([CH3:4])([CH3:3])[CH3:2].[CH:32]1([N:37]=[C:38]=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1.Cl.CCOCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:21][CH:22]=2)=[CH:11][C:10]=1[CH2:29][O:30][C:38](=[O:39])[NH:37][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1CO
Reactant: O=C=NC1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1COC(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 15 mL round bottomed flask was charged with 3-{2-hydroxymethyl-4-[2-(2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid tert-butyl ester (0.10 g, 0.23 mmol), cyclopentylisocyanate (0.15 mL, 1.38 mmol), and anhydrous CH2Cl2 (0.75 mL). A 1.0 M HCl solution in ether (0.115 mL, 0.115 mmol) was added, and the reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 24 h. The reaction mixture was diluted with CH2Cl2, (30 mL), washed with brine, dried (Na2SO4), and concentrated to an oil. The crude product was purified using radial chromatography (EtOAc:hexanes 10:90 to 35:65) to a colorless oil (0.105 g, 83%). 1H NMR (400 MHz, CDCl3) 1.42 (s, 9H), 1.56-1.65 (m, 4H), 1.94-2.04 (m, 2H), 2.37 (s, 3H), 2.46 (t, J=7.6 Hz, 2H), 2.87 (t, J=8.1 Hz, 2H), 2.96 (t, J=6.6 Hz, 2H), 3.97 (br s, 1H), 4.22 (t, J=6.6 Hz, 2H), 4.76 (br s, 1H), 5.07 (s, 2H), 6.90 (dd, J=8.3, 2.4 Hz, 1H), 6.89 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.40-7.45 (m, 3H), 7.96-7.98 (m, 2H). MS (ES) m/e 549 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=5)[C:19]([C:33]([O:35]C)=[O:34])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1>CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=5)[C:19]([C:33]([OH:35])=[O:34])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C(=O)O)cc1
Yield: 7.7 %

Procedure:
Methyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4′-(dimethylcarbamoyl)biphenyl-2-carboxylate (84 mg, 0.20 mmol) was dissolved in DMF (2.0 mL) with 1M K2CO3 (1.0 mL) and irradiated in the microwave at 150° C. for 10 minutes. Purification by reverse phase HPLC yielded 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4′-(dimethylcarbamoyl)-biphenyl-2-carboxylic acid (7.3 mg, 8%). ESI-MS m/z calc. 472.5, found 473.3 (M+1)+; retention time 2.79 minutes.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[C:11]([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])[CH:10]=1)=[O:8]>CO.[OH-].[Na+]>[C:32]([CH2:31][CH2:30][C:11]1[CH:10]=[C:9]([C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]([OH:36])=[O:2])[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)([OH:34])=[O:33]
Reactant: COC(=O)CCCC(=O)c1ccc(OCCCC/C=C/c2ccc(OC)cc2)c(CCC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C/CCCCOc2ccc(C(=O)CCCC(=O)O)cc2CCC(=O)O)cc1
Yield: 72.1 %

Procedure:
A solution of 400 mg of 5-[3-(2-methoxycarbonylethyl)-4-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-phenyl]-5-oxo-pentanoic acid methyl ester in 33 ml of methanol and 13 ml of in sodium hydroxide solution is stirred for 16 hours at room temperature. The methanol is distilled off in a vacuum, the alkaline solution is acidified with in hydrochloric acid to pH 1, shaken out with ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. 272 mg of the title compound of the melting point of 113°-114° is obtained.
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:6]=2[CH:7]=1)=[O:2].[CH3:16][Mg]Br>C1COCC1>[OH:2][CH:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:6]=2[CH:7]=1)[CH3:16]
Reactant: COC(=O)c1ccc2cc(C=O)oc2c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(C(C)O)oc2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Methyl 2-formyl-1-benzofuran-6-carboxylate (750 mg, 3.67 mmol) is dissolved in anhydrous THF (30 ml) in a dry flask under nitrogen and cooled to 0° C. Methyl magnesium bromide (2.6 ml, 3.67 mmol) is added via syringe, and the reaction is stirred overnight, allowing the ice bath to expire. The reaction is quenched with 5% HCl (70 ml) and extracted with CH2Cl2 (3×25 ml). The combined organics are dried (MgSO4), filtered, and concentrated to a yellow oil. The crude material is chromatographed over 100 g slurry-packed silica gel, eluting with 35% EtOAc/hexane. The appropriate fractions are collected and concentrated to afford 412 mg (51%) of methyl 2-(1-hydroxyethyl)-1-benzofuran-6-carboxylate as a yellow oil that solidified upon standing. MS for C12H12O4, (EI) m/z: 220 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1/[CH:11]=[CH:12]/[CH:13]=O.[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N+:16]=[N-:17].[Na].[Cl-].[NH4+]>C(O)C.CCO.CCO>[N:15](/[C:18](=[CH:13]/[CH:12]=[CH:11]/[C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N+:16]=[N-:17]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: COc1cccc(OC)c1/C=C/C=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)/C(=C\C=C\c1c(OC)cccc1OC)N=[N+]=[N-]
Temperature: -10 °C

Procedure:
Add dropwise, while stirring, a solution of 37 g (192 mmol) of (2E)-3-(2,6-dimethoxyphenyl)acrylaldehyde and 85.7 g (664 mmol) of ethyl 2-azidoacetate in 200 mL of absolute ethanol EtOH to a solution of 15.5 g (673 mmol) of sodium in 500 mL of absolute EtOH cooled to −10° C. and kept under argon, maintaining the temperature at −10° C. After stirring at −10° C. for 3 h, stir the reaction mixture for 15 h at RT, then pour into 600 mL of an aqueous solution of ammonium chloride (NH4Cl) at 30 wt. %. After filtration on a frit and rinsing with 2×200 mL of water, take up the precipitate in 600 mL of DCM, dry over Na2SO4 and concentrate under reduced pressure, which leads to 42 g of ethyl (2E,4E)-2-azido-5-(2,6-dimethoxyphenyl)penta-2,4-dienoate in the form of a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:15])([CH3:14])[CH2:9][C:10]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH:17]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])N>C(O)=O>[CH3:14][C:8]1([CH3:15])[C:9]2[C:27]3[C:19](=[C:20]([C:21]([OH:23])=[O:22])[CH:24]=[CH:25][CH:26]=3)[NH:17][C:10]=2[C:11]2[C:7]1=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2
Reactant: CC1(C)CC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: O=CO
Product: CC1(C)c2ccc([N+](=O)[O-])cc2-c2[nH]c3c(C(=O)O)cccc3c21
Yield: 18.5 %

Procedure:
6-Nitro-3,3-dimethyl-1-indanone (0.612 g, 2.98 mmol) [Smith, J. G. et al. Org. Prep. and Proc. Int. 1978, 10(3), 123-131] and 2-hydrazinobenzoic acid hydrochloride (0.562 g, 2.98 mmol) in formic acid (2 mL, 96%) were irradiated for two minutes in a closed cap Teflon vessel of a microwave oven (700W). The mixture was vacuum filtered, and the crude product was chromatographed (hexane/ethyl acetate 1:1) and triturated with petroleum ether/diethyl ether. Drying in vacuo afforded 0.178 g (19%) of the title compound as a yellow solid: mp 310° C. (dec); 1H NMR (DMSO-d6): δ 13.43 (s, 1H), 11.85 (s, 1H), 8.95 (s, 1H), 8.12 (d, 1H), 7.98 (d, 1H), 7.81 (m, 2H), 7.19 (t, 1H), 1.59 (s, 6H); IR (KBr): 3460, 1670 cm−1; MS (m/z) 322 (M+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([CH2:12][OH:13])=[CH:6][C:5]=1[O:14][CH3:15].IC.[C:18](OCC)(=O)C>CN(C)C=O>[Br:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([CH2:12][O:13][CH3:18])=[CH:6][C:5]=1[O:14][CH3:15]
Reactant: COc1cc(CO)cc(OC)c1Br
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCc1cc(OC)c(Br)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in oil; 24.7 g) was added to a solution of (4-bromo-3,5-dimethoxyphenyl)methanol (118.8 g) in N,N-dimethylformamide (960 mL) while cooling with ice, and after stirring for 10 minutes, iodomethane (41.7 mL) was added dropwise, the temperature was increased to room temperature and stirring was continued for 1 hour. The obtained reaction mixture was poured into ice water (2.5 L), extraction was performed with ethyl acetate, the extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (121.3 g) was obtained as a colorless oil from the n-hexane:ethyl acetate (4:1) fraction.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[N:33]=[C:32]([C:34]([OH:36])=[O:35])[CH:31]=[CH:30][CH:29]=2)[CH2:24][CH:23]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:43].C(OCC)(=O)C.C(OC(C)C)(C)C>C(OCC)(=O)C>[ClH:43].[C:11]1([C@H:9]([NH:8][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[C:32]([C:34]([OH:36])=[O:35])[CH:31]=[CH:30][CH:29]=3)[CH2:24][CH:23]2[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2cccc(C(=O)O)n2)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: C[C@@H](NCC1CCN(c2cccc(C(=O)O)n2)CC1c1ccccc1)c1cccc2ccccc12
Reaction time: 2 h

Procedure:
To a solution of 75 mg of the crude 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]pyridine-2-carboxylic acid in 2.0 mL of ethyl acetate was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 2 hours. To the reaction mixture was added diisopropylether, and the resulting precipitate was then collected by filtration, and dried under reduced pressure to obtain 50 mg of 6-[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]pyridine-2-carboxylic acid hydrochloride as a pale yellow solid.