Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:6]([O:8][C@@H:9]1[C@@H:14]2[C@@H:15]([CH2:20][CH2:21][C@H:22]3[O:28][C:26](=[O:27])[CH2:25][C@H:24]([OH:29])[CH2:23]3)[C@@H:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[CH:12][C@H](C)[CH2:10]1)=[O:7])([CH3:5])[CH3:4].[OH-:31].[Na+:32].C(Cl)Cl.[C:36](#N)[CH3:37]>O.CC(C)=O>[CH3:1][CH2:2][C:3]([C:6]([O:8][C@@H:9]1[C@@H:14]2[C@@H:15]([CH2:20][CH2:21][C@@H:22]([OH:28])[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([O-:27])=[O:31])[C@@H:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[CH:12][C@H:36]([CH3:37])[CH2:10]1)=[O:7])([CH3:4])[CH3:5].[Na+:32]
Reactant: CC#N
Reactant: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)[O-])[C@H]21
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.8 %

Procedure:
1.43 g (3.42 mmole) of simvastatin lactone was dissolved in 10 mL acetonitrile and treated with water (5 mL) and sodium hydroxide (151 mg, 3.78 mmole). The reaction was stirred at room temperature for 3 days, at which time analytical thin-layer chromatography using 4:1 methylene chloride:acetone eluent indicated essentially complete conversion of the starting lactone to a more polar product. The reaction mixture was then diluted to 50 mL with 1:1 acetonitrile:water, frozen and lyophilized to afford 1.22 g (2.66 mmole, 77.8%) of simvastatin sodium as a fluffy white solid. The 400 MHz 1H nuclear magnetic resonance (NMR) spectrum was consistent with the sodium carboxylate product. 1H NMR (Me2SO-d6) δ 7.6 (br s, 1H), 5.95 (d, 1H), 5.8 (in, 1H), 5.5 (s, 1H), 5.1 (s, 1H), 4.6 (s, 1H), 3.7 (br s, 1H), 3.5 (br s, 1H), 2.3 (m, 2H), 2.2 (d, 1H), 2.0 (m, 2H), 1.8 (m, 2H), 1.6–1.3 (5H), 1.2 (br s, 3H), 1.0 (9H), 0.80 (m, 3H), 0.75 (m, 3H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=2)O1.[CH3:28][O:29][C:30](=[O:41])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[C:32]=1Br.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][O:29][C:30]([C:31]1[C:32]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:22])=[O:23])=[CH:13][CH:14]=2)=[C:33]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:35][CH:36]=1)=[O:41]
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1cccc([N+](=O)[O-])c1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
Heat the mixture of propane-2-sulfonic acid {2-[4-{4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiophen-3-yl}-amide(662 mg, 1.65 mmol), 2-bromo-3-nitro-benzoic acid methyl ester (390 mg, 1.5 mmol), Na2CO3(2M, 2.2 mL, 4.5 mmol) and Pd(PPh3)4 (260 mg, 0.26 mmol) and 15 ml of 1,4 dioxane under N2 to 80° C. overnight. After cooling to room temperature, dilute with diethyl ether (200 mL). Wash with water, saturated aq. sodium chloride, and dry over MgSO4. Remove solvent and purify by flash chromatography (Silica gel-hexane/EtOAc) to provide 6-nitro-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-2-carboxylic acid methyl ester (250 mg). MS (m/e): 478.7(M+1).
Reaction SMILES: [CH3:1][N:2]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:3](=[O:24])[CH2:4][CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[N+:21]([O-])=O.S1C=CC=C1.[H][H]>[Pd].CO>[NH2:21][C:9]1[CH:10]=[CH:11][C:12]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][C:8]=1[CH2:7][NH:6][CH2:5][CH2:4][C:3]([N:2]([CH3:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24]
Reactant: [H][H]
Reactant: CN(C(=O)CCNCc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])c1ccccc1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CN(C(=O)CCNCc1cc(Oc2ccccc2)ccc1N)c1ccccc1

Procedure:
A mixture of N-methyl-3-(2-nitro-5-phenoxy-benzylamino)-N-phenyl-propionamide (2 g, 0.0049 mol), 10% palladium on carbon (1 g), and thiophene solution (1 mL) in 150 mL of MeOH was hydrogenated until 3 equivalents of hydrogen were consumed. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography on a Biotage. The product containing fractions were collected and concentrated to yield a residue.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([CH3:18])[CH:9]=2)=[CH:6][C:5]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[CH:4][N:3]=1.O[Li].O>C1COCC1.CO.O>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH3:18])[CH:9]=2)=[CH:6][C:5]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3cnn(C)c3)cnc2N)cc1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(-c2cc(-c3cnn(C)c3)cnc2N)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of methyl 4-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-methylbenzoate (1.20 g, 3.72 mmol) in THF/MeOH/H2O (1:1:1, 36 mL) was added LiOH—H2O (0.234 g, 5.58 mmol). The solution was stirred at room temperature overnight. The pH was adjusted to 3-5, optimally 4. All the organic solvents were removed by reduced pressure. EtOAc was added to triturate out all the impurities. Water was added and the mixture was stirred for 30 min. Solid was filtered and washed well with 50% of ether and water. The solid was then azotropied on rotovap with toluene to provide about 800 mg of desired acid in 69.7% yield. LCMS (m/z): 309.2 (MH+), 0.50 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9].Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[O:9])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: OCCCCCCCl
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(/C=C/C(=O)OCCCCCCO)cc1OC
Temperature: 80 °C
Reaction time: 19 h

Procedure:
A solution consisting of 0.72 ml of 1,8-diazobicyclo[5.4.0]undec-7-ene (1.5-5) and 5 ml of dimethylformamide was added dropwise to a solution of 1.0 g of (E)-3,4-dimethoxycinnamic acid in 10 ml of dimethylformamide in the course of 10 minutes at room temperature. Thereafter, the reaction mixture was heated to 80° C., 0.18 g of tetrabutylammonium iodide and 0.71 ml of 6-chloro-1-hexanol were then added in succession and the reaction was then allowed to proceed for 19 hours. Thereafter, the reaction mixture was cooled to room temperature and partitioned between diethyl ether and 1 N hydrochloric acid and the organic phase was washed several times with saturated sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered and evaporated down. Chromatography of the residue over 150 g of silica gel with 3:2 toluene/ethyl acetate gave 1.35 g of 6-hydroxyhexyl 3(E)-(3,4-dimethoxyphenyl)acrylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[H-].[Na+].[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:35])=[O:34])[CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2cn(S(=O)(=O)c3ccccc3)c3ccc(F)cc23)CC1
Reaction time: 0.5 h

Procedure:
A stirred solution of tert-butyl 4-[(5-fluoro-1H-indol-3-yl)methyl]-1-piperidinecarboxylate (665 mg, 2.0 mmol) in tetrahydrofuran is treated with NaH (60% in mineral oil, 120 mg, 3.0 mmol) portion-wise, under nitrogen, at room temperature, stirred for 0.5 hr, treated with benzenesulfonyl chloride (0.38 ml, 3.0 mmol), stirred for 18 hr under nitrogen at room temperature, quenched with water and diluted with ethyl acetate. The resultant phases are separated and the organic phase is washed with water and saturated NaCl, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane, 2/8) to afford the title compound as a white solid, 740 mg, mp 155-157° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][CH2:16][NH2:17])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:27][S:28]([Cl:31])(=[O:30])=[O:29]>C(Cl)Cl>[ClH:31].[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][CH2:16][NH:17][S:28]([CH3:27])(=[O:30])=[O:29])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:19][CH3:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCCN(CCC)C1CCc2cccc(CCN)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCN(CCC)C1CCc2cccc(CCNS(C)(=O)=O)c2C1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.2 g (4.4 mmol) of 2-dipropylamino-8-(2-aminoethyl)-1,2,3,4-tetrahydronaphthalene and 1.21 g (8.8 mmol) of potassium carbonate were initially introduced into 20 ml of methylene chloride. 550 mg (4.8 mmol) of methanesulphonyl chloride were then added dropwise at 25° C. The mixture was stirred overnight at room temperature. The mixture was then filtered, and the filtrate was washed once with water, dried over sodium sulphate and evaporated. Diethyl ether was added to the residue, methylene chloride was added until everything was dissolved, and the hydrochloride was precipitated using ethereal hydrochloric acid. The product was filtered off under suction and dried at 40° C. in a high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6](=[O:26])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=3[Cl:19])[NH:12][C:11]=2[C:21]([O:23]CC)=[O:22])=[CH:4][CH:3]=1.[OH-].[Li+].O1CCCC1.O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:26])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=3[Cl:19])[NH:12][C:11]=2[C:21]([OH:23])=[O:22])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccc(Cl)cc1

Procedure:
Mix 3-[(p-chlorophenacyl)methylamino]-2-carbethoxy-4,6-dichloroindole (1.3 g, 3.1 mmol), excess lithium hydroxide, tetrahydrofuran and water and stirovernight. Dilute with ethyl acetate and separate the layers. Dry the organic phase over magnesium sulfate, filter and concentrate in vacuo to yield the title compound; mp 279°-283° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.[N:21]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH4+].[Cl-].CCN(C(C)C)C(C)C>CS(C)=O>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:21])=[O:5]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: NC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.5 %

Procedure:
To a solution of 2-amino-3-nitrobenzoic acid (5.00 g, 27.47 mmol) in DMSO (30 mL) were added BOP (18.21 g, 41.21 mmol), NH4Cl (4.41 g, 82.41 mmol) and DIPEA (10.63 g, 82.41 mmol) and the reaction mixture was stirred at rt for 14 h and it was quenched with ice-water and the precipitate obtained was filtered, washed with Et2O and dried to afford 4.90 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.48 (br s, 2H), 8.19-8.17 (m, 2H), 7.96-7.94 (d, J=7.2 Hz, 1H), 7.62 (br s, 1H), 6.71-6.65 (t, J=7.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:31][Si](C(C)(C)C)(C)C)[CH2:16][NH:17][C@H:18]([CH3:30])[CH2:19][C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])=[CH:11][C:10]=1[CH2:39][OH:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[NH4+]>CO.O>[NH3:17].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:31])[CH2:16][NH:17][C@H:18]([CH3:30])[CH2:19][C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])=[CH:11][C:10]=1[CH2:39][OH:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1
Agent: [F-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(C[C@@H](C)NC[C@H](O)c2ccc(OCc3ccccc3)c(CO)c2)c1
Product: N
Yield: 171.3 %

Procedure:
A solution of methyl 3-{(2R)-2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]propyl}benzoate (Preparation 62) (10 g, 17.74 mmol) and ammonium fluoride (6.57 g, 177 mmol) in methanol (180 ml) and water (60 ml) was heated at 40° C. for 18 hrs. The methanol was removed in vacuo and the remaining aqueous layer extracted with dichloromethane (2×100 ml). The combined organic layers were dried (sodium sulfate), filtered and evaporated in vacuo. The resulting oil was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (95:5:0.5, by volume) to give the title compound (6.83 g) as a pale yellow gum. 1H NMR (400 MHz, CD3OD): δ=7.83-7.82 (1H, d), 7.78 (1H, s), 7.47-7.45 (2H, m), 7.39-7.28 (6H, m), 7.11-7.10 (1H, d), 6.89-6.87 (1H, d), 5.11 (2H, s), 4.65 (2H, s), 4.65-4.62 (1H, m), 3.88 (3H, s), 2.98-2.89 (2H, m), 2.79-2.64 (3H, m), 1.09-1.08 (3H, d) ppm. LRMS (electrospray): m/z [M+H]+ 450, [M+Na]+ 472, [M−H]− 448.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:4](I)[CH:3]=1.CN(C)C=O.[CH2:24]([O:27][CH:28]([CH3:32])[C:29]([OH:31])=[O:30])[C:25]#[CH:26].[CH2:33](NCC)[CH3:34]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:33]([O:30][C:29](=[O:31])[CH:28]([O:27][CH2:24][C:25]1[N:8]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:5]2[C:4]([CH:26]=1)=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH3:32])[CH3:34]
Reactant: O=S(=O)(Nc1ccc(Cl)cc1I)c1ccccc1
Reactant: CCNCC
Reactant: C#CCOC(C)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)OCc1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 130 °C

Procedure:
A mixture of 600 mg (1.52 mM) of N-(4-chloro-2-iodophenyl)benzenesulfonamide (Preparation 120) and 0.5 ml of dimethylformamide is prepared in a microwave reaction tube and 14 mg (0.076 mM) of cuprous iodide, 27 mg (0.038 mM) of bis(triphenylphosphine)dichloropalladium, 357 mg (2.3 mM) of the ethyl ester of 2-(2-propynyloxy)propanoic acid and, finally, 0.5 ml of diethylamine are added. The mixture is heated by microwaves at 130° C. for 15 min and then cooled and hydrolyzed with 10 ml of water. The mixture is extracted three times with 15 ml of ethyl acetate and the combined organic phases are washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (95/5; v/v) as the eluent to give 0.44 g of the expected compound in the form of a yellow oil (yield=69%).
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:28]=[CH:27][C:14]([CH:15]=[C:16]([C:22]([O:24]CC)=[O:23])C(OCC)=O)=[C:13]([O:29][CH3:30])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C-:31]#[N:32].[K+]>O>[CH2:3]([O:10][C:11]1[CH:28]=[CH:27][C:14]([CH:15]([C:31]#[N:32])[CH2:16][C:22]([OH:24])=[O:23])=[C:13]([O:29][CH3:30])[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1OC)C(=O)OCC
Reactant: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(OCc2ccccc2)ccc1C(C#N)CC(=O)O
Temperature: 70 °C
Yield: 100 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with methanol (20 mL) and water (5 mL). To the stirred solvent was added diethyl [4-(benzyloxy)-2-methoxybenzylidene]propanedioate (0.775 g, 2.02 mmol), followed by potassium cyanide (0.262 g, 4.04 mmol). The RM was heated at 70° C. for 2 h. The RM was concentrated, diluted with saturated NaHCO3 solution (50 mL) and washed with ethyl acetate (50 mL×2). The aqueous layer was acidified to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate (50 mL×2). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid. (0.62 g, yield: 100.0%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1>ClCCl>[CH3:8][O:9][C:10]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: COc1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
Trifluoroacetic acid (5 eq) was added to a solution of tert-butyl 4-(2-methoxy-4-nitrophenoxy)piperidine-1-carboxylate (200 mg, 0.57 mmol, 1 eq) in dichloromethane, stirring at room temperature for 1 hour. The solvent was then evaporated, the residue was brought to pH 10 with sat. aq. Na2CO3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and evaporated to afford the product 4-(2-methoxy-4-nitrophenoxy)piperidine as a light yellow solid (137.3 mg, 96%). LC/MS (m/z): 253.2 (MH+), Rt 1.81 minutes.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:24](OC)(OC)[CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:25]([C:24]1[N:10]([CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCC(OC)(OC)OC
Reactant: Nc1cnc2ccccc2c1NCCOc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCOc1ccccc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
N4-(2-Phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol), xylenes (150 ml), and trimethylorthovalerate (2.5 ml, 14.3 mmol) were combined under an atmosphere of nitrogen and heated at reflux temperature for 4 days. The external heat was increased and approximately 35 ml of xylenes was removed by distillation. The reaction was slowly cooled to room temperature and a precipitate formed. The solid was recovered by vacuum filtration to yield 2.4 g of 2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline as a light tan crystalline solid.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:17]=1N)=[O:12])[CH3:9].C(OC(C1C(N)=NN(C2CCC2)C=1)=O)C.[ClH:38]>C(#N)C>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:17]=1[Cl:38])=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cnn(C2CCC2)c1N
Reactant: Cl
Agent: CC(C)(C)ON=O
Agent: CCOC(=O)c1cn(C2CCC2)nc1N
Solvent: CC#N
Product: CCOC(=O)c1cnn(C2CCC2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl nitrite (5.1 mL, 38.7 mmol), cuprous chloride (3.8 g, 38.7 mmol), and anhydrous acetonitrile (100 mL) was added a mixture of 5-amino-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ester and 3-amino-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ester (from last step without further purification) in anhydrous acetonitrile (50 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h and then at 60° C. for 2 h. The mixture was cooled to room temperature and then poured into 6N HCl (50 mL) and extracted with dichloromethane. The aqueous layer was extracted three times with dichloromethane. After the combined organic layers were concentrated in vacuo, the crude residue was purified by flash chromatography eluting with a gradient of 10-20% ethyl acetate/hexanes, then 20% ethyl acetate/hexanes. The desired fractions were concentrated in vacuo and dried under vacuum to give 5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ester (eluted first, 610 mg, 10.3%) and 3-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ester (eluted later, 147 mg, 2.5%). LRMS m/z calcd for C10H13ClN2O2 (M+H) 229.1, found 229.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@@H:25]([CH3:34])[C@H:26]([OH:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:36](Cl)(=[O:38])[CH3:37]>>[CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:36](=[O:38])[CH3:37])[C@@H:25]([CH3:34])[C@H:26]([OH:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H](C)[C@H](O)c2ccccc2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@@H](C)[C@H](O)c2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {2′-[((1S,2R)-2-hydroxy-1-methyl-2-phenyl-ethylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]([CH3:25])=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:32]([NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)([CH3:34])[CH3:33]>>[CH:36]1([N:35]([CH:32]([CH3:34])[CH3:33])[C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([N:13]3[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:15][CH2:14]3)[C:17]=2[CH3:25])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)NC1CCCCC1
Reactant: Cc1c(C(=O)O)cccc1N1CCN(CCC(c2ccccc2)c2ccccc2)CC1
Product: Cc1c(C(=O)N(C(C)C)C2CCCCC2)cccc1N1CCN(CCC(c2ccccc2)c2ccccc2)CC1

Procedure:
Step (d) of Example 1 was repeated, except that the compound prepared just above in step (c) was used instead of 3-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-methylbenzoic acid and N-isopropylcyclohexylamine was used instead of N-methylbenzylamine. Thus, the title compound was prepared.