Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])([O-])=O.[Nd+3:5].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].C(N(CC)CC)C>C(O)C>[Nd:5].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: [Nd+3]
Agent: COc1ccccc1C(=O)O
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: [Nd]
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
The compound was synthesized by the same method as that for Synthesis Example 1-2 above, that is, after forming a triethylamine salt of 2-methoxybenzoic acid in anhydrous ethanol, an ethanol solution of neodymium nitrate was added while stirring. Specifically, a reactor similar to that of 1-1 was used to stir a slurry solution obtained by adding 100 ml of an anhydrous ethanol to 45.65 g (0.3 mol) of 2-methoxybenzoic acid, while dripping 30.4 g (0.3 mol) of triethylamine while maintaining at 20-30° C. by cooling in an ice water bath. After dripping about one-third of the triethylamine, the slurry disappeared and became transparent. After dripping, the solution was heated for 30 minutes at 40° C. to prepare a transparent synthesis solution of 2-methoxybenzoic acid-triethylamine salts. Next, while stirring this synthesis solution and holding at 25° C., a solution obtained by dissolving 43.8 g of neodymium nitrate into 120 ml of ethanol was dripped in. Upon completion of dripping, the solution was heated to 40° C., began to cloud after 40 minutes, and the clouding increased with time. After another 20 minutes, it became an extremely thick slurry solution, so 100 ml of ethanol were further added, and the solution was stirred for another hour at 40° C., then cooled to end the reaction. Next, crystals obtained by filtering this slurry solution were added to 200 ml of methanol, stirred and washed, then refiltered, and 200 ml of methanol were once again added to the crystals, stirred and washed, then filtered. The resulting crystals were dried under reduced pressure at 50° C., to obtain 50.83 g of a neodymium salt of 2-methoxybenzoic acid (yield 85%).
Reaction SMILES: [Na].[OH:2][C:3]1[C:8]([CH2:9][CH2:10][CH3:11])=[C:7]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]=1[C:25](=[O:27])[CH3:26].[Br:28][CH2:29][CH2:30][CH2:31]Br.CCC(C)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:25]([C:4]1[CH:5]=[CH:6][C:7]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[N:22][N:23]([CH2:31][CH2:30][CH2:29][Br:28])[N:24]=3)=[CH:16][CH:15]=2)=[C:8]([CH2:9][CH2:10][CH3:11])[C:3]=1[OH:2])(=[O:27])[CH3:26]
Reactant: CCCc1c(COc2ccc(-c3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CCCc1c(COc2ccc(-c3nnn(CCCBr)n3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
1-[2-Hydroxy-3-propyl-4-((4-(1H-tetrazol-5-yl)phenoxy)methyl)phenyl]ethanone sodium salt (5 g, 0.013 mol), 1,3-dibromopropane (3.5 g, 0.18 mol), and MEK (50 ml) were combined potassium carbonate (4.15 g, 0.025 mol) potassium was added and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The volume of the concentrate was doubled by the addition of water and the resultant solution was extracted with ethyl acetate (3×). The ethylacetate layers were combined, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed by HPLC (preparatory-scale, silica gel column, eluted with a mixture of 9:1 toluene:ethyl acetate) to yield 5.0 g, 82% yield of the title product: n.m.r. (300 MHz CDCl3) δ: 1.0 (t, 3H); 1.6 (m, 2H); 2.6 (s and t, 5H); 2.7 (t, 2H); 3.5 (t, 2 H); 4.8 (t, 2H); 5.15 (s, 2H); 7.1 (d, 2H); d, 1H); 7.6 (d, 1H); 8.1 (d, 2H); 12.7 (s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8](=[CH2:11])[C:9]#[N:10])[CH2:3][CH2:2]1.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]CC.[Na+].Cl>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]2[CH2:11][N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:19][C:9]2=[NH:10])[CH2:3][CH2:2]1
Reactant: C=C(C#N)CN1CCOCC1
Reactant: NNc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N=C1NN(c2ccccc2)CC1CN1CCOCC1

Procedure:
α-Morpholinomethylacrylonitrile (54g) and phenylhydrazine (37g) were boiled under reflux with a solution of sodium ethoxide (7.5g sodium) in ethanol (250 ml) for two hours. A solid product was formed during the reaction. Dilute hydrochloric acid (160 ml 2N) was added and the solution was evaporated to dryness. The solid residue was extracted with dry ethanol and the product crystallised from the ethanol as colourless plates (melting point 204-5° C).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:20](Cl)(=[O:22])=[O:21])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1.[OH-].[NH4+:27]>O1CCOCC1>[F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:20]([NH2:27])(=[O:22])=[O:21])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COc1ccc2cc(S(=O)(=O)Cl)ccc2c1C(=O)c1ccc(F)cc1
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2cc(S(N)(=O)=O)ccc2c1C(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
A solution of 5-(4-fluorobenzoyl)-6-methoxy-2-naphthalenesulfonyl chloride (5.39 g, 14.2 mmol), [prepared as described in step 2 above], in dioxane (100 ml), was cooled in an ice bath under nitrogen, and concentrated ammonium hydroxide (20 ml) was added dropwise. After 1 h, the dioxane was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (gradient elution, 20-60% ethyl acetate/hexane) and then recrystallized from ethyl acetatelhexane to afford 2.7 g of 5-(4-fluorobenzoyl)-6-methoxy-2-naphthalenesulfonamide as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][C@@H:15]([CH3:20])[C:16]([F:17])([F:19])[F:18])=[CH:12][N:11]=[C:10]([C:21]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([C:25]([F:24])([F:33])[F:34])[CH:30]=3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: NCc1cc(C(F)(F)F)no1
Reactant: C[C@H](Oc1cnc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Product: C[C@H](Oc1cnc(C(=O)NCc2cc(C(F)(F)F)no2)nc1-c1ccc(Cl)cc1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1 using (S)-4-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrimidine-2-carboxylic acid (example AQ) and 3-trifluoromethyl-isoxazol-5-methanamine (example BA) as starting materials; LC-MS (UV peak area/ESI) 100%, 495.0965 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CS(=O)(=O)OC1CCOCC1
Reactant: O=Cc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(I)ccc1OC1CCOCC1
Yield: 84.6 %

Procedure:
In a manner similar to the method described in example 4a, 5-iodosalicylaldehyde (3 g, 12.1 mmol) (Aldrich) reacted with methanesulfonic acid tetrahydropyran-4-yl ester (4 g, 22 mmol) and K2CO3 in N,N-dimethylformamide to give 5-Iodo-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde as a yellow solid (Yield 3.4 g, 85%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].Br[CH2:27][CH2:28][CH2:29][Cl:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: ClCCCBr
Reactant: COc1ccc(Oc2ccnc3cc(O)c(OC)cc23)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccnc3cc(OCCCCl)c(OC)cc23)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
1-{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-ethanone (100 mg), 1-bromo-3-chloropropane (138 mg), and potassium carbonate (204 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (123 mg, yield 34%).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[C:35]([Si:39]([CH3:50])([CH3:49])[O:40][CH2:41][CH2:42][N:43]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44]1)([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[C:35]([Si:39]([CH3:50])([CH3:49])[O:40][CH2:41][CH2:42][N:43]1[CH:47]=[CH:46][C:45]([NH:48][C:8](=[O:10])[C@@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:44]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionic acid (92 mg, 0.32 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 190 μL, 0.35 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was cooled to 0° C. and 2,6-lutidine (80 μL, 0.64 mmol) was added to the flask and it was stirred for 15 min. To this was then added a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 78 mg, 0.32 mmol) in methylene chloride (1 mL) and the reaction was allowed to warm up to 25° C. and stirred for 2 h. After this time the reaction quenched with a small amount of methanol and then diluted with methylene chloride. The reaction was then transferred to a separatory funnel and washed with 1 N aqueous hydrochloric acid solution (1×10 mL) and then a saturated brine solution (1×10 mL). The organic layer was then dried over sodium sulfate and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40M column, silica gel, 40% ethyl acetate/hexanes) (40S column, Silica gel, 20% ethyl acetate/hexanes) to afford N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionamide as a colorless gum: [α]25589=−14.5° (c=0.22, methanol); ES-HRMS m/e calcd for C26H38N3O2SiF3 (M+H)+ 510.2758, observed 510.2749; 1H NMR (400 MHz, DMSO-d6) δ ppm −0.09 (s, 6H, 2×SiCH3), 0.77 (s, 9H, 3×CH3), 1.06-1.18 (m, 2H, CH2), 1.37-1.79 (m, 8H, 4×CH2), 2.08-2.18 (m, 1H, CH), 3.84 (t, J=5.1 Hz, 2H, OCH2), 3.90 (dd, J=9.4, 5.3 Hz, 1H, ArCH), 4.04 (t, J=5.1 Hz, 2H, NCH2), 6.41 (d, J=2.3 Hz, 1H, Ar), 7.51 (d, J=2.3 Hz, 1H, Ar), 7.54-7.72 (m, 4H, Ar), 10.72 (s, 1H, NH).
Reaction SMILES: [CH2:1]([N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[P:28](Cl)(=[O:43])([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][P:28]([O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([O:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:43])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](CO)C(=O)O
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](COP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)O
Reaction time: 3 h
Yield: 80.3 %

Procedure:
In 30 ml of dried methylene chloride was dissolved 3.75 g of benzyl N-t-butoxycarbonyl-D-serine, and 1.23 ml of pyridine, 1.86 g of 4-dimethylaminopyridine, and 4.09 g of diphenyl phosphorochloridate were successively added thereto at room temperature, followed by stirring at that temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 2% acetone-containing chloroform) to obtain 5.38 g of benzyl N-t-butoxycarbonyl-O-diphenylphosphono-D-serine as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[N:7]([N:8]=[C:9]3[C:14]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25]C(C)(C)C)=O)[CH2:19][CH2:18]1.[C:30]1([CH2:36]C(Cl)=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([CH2:36][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([CH2:16][N:3]3[CH2:4][CH2:5][CH2:6][N:7]4[N:8]=[C:9]5[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]5)=[C:15]4[C:2]3=[O:1])[CH2:22][CH2:21]2)=[O:25])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCCn3nc4ccccc4c3C2=O)CC1
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)N1CCC(CN2CCCn3nc4ccccc4c3C2=O)CC1

Procedure:
The product was prepared using the method described in example 2e), using tert-butyl 4-[(1-oxo-4,5-dihydro-1H-[1,4]diazepino[1,2-b]indazol-2(3H)-yl)methyl]piperidine-1-carboxylate (example 16a) and benzeneacetyl chloride as reagents. The product was purified by flash chromatography on silica gel, using the mixture chlorofom:methanol in a ratio of 9:1 as eluent. Thus, 141 mg of 2-{[1-(phenylacetyl)piperidin-4-yl]methyl}-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-b]indazol-1-one were obtained.
Reaction SMILES: [O:1]([CH:8]1[CH2:17][CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C:18]([OH:20])=O)[CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:50][CH2:51][C:52]1[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=1[CH3:58]>ClCCl>[OH:60][C:53]1[C:52]([CH2:51][NH:50][C:18]([C:12]2[CH:11]=[CH:10][C:9]3[CH:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=2)=[O:20])=[C:57]([CH3:58])[CH:56]=[C:55]([CH3:59])[N:54]=1
Reactant: O=C(O)c1ccc2c(c1)CCCC2Oc1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc3c(c2)CCCC3Oc2ccccc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
To a solution of 5-phenoxy-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (0.032 g, 0.12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.06 g, 0.3 mmol) and N-hydroxybenzotriazole (0.03 g, 0.22 mmol) in dichloromethane (10 mL) was added triethylamine (0.03 g, 0.3 mmol). The reaction mixture was stirred for 15 minutes at room temperature, then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.03 g, 0.2 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water (10 mL×3). The organic phase was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give pure product N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-5-phenoxy-5,6,7,8-tetrahydronaphthalene-2-carboxamide (Compound I-52) as a white solid (0.031 g, 63%). LRMS (M+H+) m/z: calcd 402.19. found 402. 1H NMR (300 MHz, CD3OD): δ 7.59 (s, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.28 (t, J=7.2 Hz, 2H), 7.02-6.92 (m, 3H), 6.10 (s, 1H), 5.43 (t, J=4.5 Hz, 1H), 4.48 (s, 2H), 2.90-2.82 (m, 2H), 2.37 (s, 3H), 2.24 (s, 3H), 2.08-1.83 (m, 4H).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=O)C.[CH2:12]([OH:14])[CH3:13].[OH-].[K+].[ClH:17]>CCOCC>[ClH:17].[Cl:17][C:8]1[CH:9]=[CH:10][C:12]([O:14][CH:9]2[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)=[CH:13][CH:7]=1
Reactant: CCOC(=O)N1CCCCC1
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: Clc1ccc(OC2CCNCC2)cc1

Procedure:
12.1 ml. of ethylchloroformate are added to a solution of 19.4 g of 1-benzyl-4-(p-chlorophenoxy)piperidine in 220 ml. of benzene and the solution is refluxed for 18 hours. The benzene and benzylchloride is removed under reduced pressure to give the N-ethoxycarbonylpiperidine as an uncrystallizable yellow oil. The N-ethoxycarbonylpiperidine is dissolved in 210 ml. of ethanol and 130 ml. of 45% aqueous potassium hydroxide are added. The solution is refluxed for 12 hours under nitrogen, cooled, most of the ethanol is removed under reduced pressure and the resultant oily dispersion is extracted with ether. The ether phase is extracted with 3 N hydrochloric acid, the acid extract is basified with 6N sodium hydroxide, and the basic solution is extracted with benzene. The benzene is dried and removed under reduced pressure to give a colorless oil. The oil is dissolved in 200 ml. of ether, the solution is cooled and stirred and 200 ml. of a saturated ethereal-HCl solution is slowly added. The salt forms and is collected. The salt is recrystallized from absolute ethanol to give 4-(p-chlorophenoxy)piperidine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[CH:19]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:21])[CH3:20].C(Cl)Cl.C(N(CC)CC)C>>[CH:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)=[CH:25][CH:24]=1)([CH3:21])[CH3:20]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccc(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
(R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (3 g, 0.01 mol), 4-isopropoxyphenylboronic acid (5 g, 0.03 mol), and cupric acetate (2.55 g, 0.0140 mol) were placed in a vial followed by methylene chloride (100 mL, 2 mol) and finally triethylamine (9.78 mL, 0.0702 mol) at 23° C. The flask was then purged with nitrogen, sealed and stirred at room temperature overnight. The reaction was allowed to stir for 16 hours. Reaction was then heated to 50° C. for two hours. The reaction mixture was then cooled to RT and filtrated and the crude material was then purified via chromatography (SiO2, 40 g, 0-75% EtOAC/Hexane) to give 2.4 g of the desired product as a colorless solid. Material was used without additional purification. ESI-MS: 378 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.F[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][C:2]1[N:3]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2ccnc2C)cc1
Temperature: 120 °C
Yield: 34 %

Procedure:
A mixture of 2-methylimidazole (50 g, 0.6 mol), ethyl 4-fluorobenzoate (100 g, 0.6 mol) and potassium carbonate (415 g, 3 mol) in dry DMSO (1.5 l ) was heated at 120° C. for 66 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into ice-cold water (1 l ), and extracted with Et2O (750 ml×2). The organic phase was washed with water (500 ml) and brine (500 ml), dried over MgSO4 and evaporated. The residual solid was recrystallized from ethyl acetate-hexane to give the titled compound (47 g, 33%) as yellow needles.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([CH3:21])[C:13]([N:18]=[C:19]=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=1.CCOC(C)=O>CSC>[CH3:21][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:20]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: Cc1ccccc1N=C=O
Solvent: CCOC(C)=O
Solvent: CSC
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Reaction time: 1 h

Procedure:
To a suspension of p-aminophenylacetic acid (56.8 g, 376 mmol) in DMS (150 mL) was added o-tolyl isocyanate (50 g, 376 mmol) dropwise. The reaction mixture was allowed to stir 1 h, and was poured into EtOAc (1.75 L) with stirring. The precipitate was collected and washed with EtOAc (400 mL) and MeCN (400 mL) to provide oMePUPA (80 g, 75%). ESMS M/z (M+H+) 285.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:9]#[C:10][C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:15]=1.FC1C=CC(N2C(C(OCC)=O)=CN=C2I)=CC=1.C(C1C=CC=CC=1[C:54]([F:57])([F:56])[F:55])#C.C(NC(C)C)(C)C>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.[Cu]I.C1COCC1>[F:27][C:24]1[CH:23]=[CH:22][C:21]([N:12]2[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:15]=[C:11]2[C:10]#[C:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:54]([F:57])([F:56])[F:55])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnc(C#Cc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Reactant: C#Cc1ccccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCOC(=O)c1cnc(I)n1-c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1cnc(C#Cc2ccccc2C(F)(F)F)n1-c1ccc(F)cc1

Procedure:
Ethyl 1-(4-fluorophenyl)-2-((2-(trifluoromethyl)phenyl)ethynyl)-1H-imidazole-5-carboxylate (46) was prepared in a similar manner as that described for the synthesis of compound 42 using ethyl 1-(4-fluorophenyl)-2-iodo-1H-imidazole-5-carboxylate (38) (900 mg, 2.5 mmol), 1-ethynyl-2-(trifluoromethyl)benzene (0.42 mL, 3.0 mmol), PdCl2(PPh3)2 (88 mg, 0.13 mmol), copper (I) iodide (23 mg, 0.13 mmol), diisopropyl amine (7 mL), and THF (50 mL).
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[O:12])[CH2:10][CH3:11]>CC(C)=O>[CH3:3][CH:13]([C:9](=[O:12])[CH2:10][CH3:11])[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCC(=O)CC(=O)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCC(=O)C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Methyl iodide (57 ml) and K2CO3 (127 g) were added to a solution of methyl propionylacetate (100 g) in acetone (800 ml) while cooling on ice. The reaction solution was stirred for 96 hours at room temperature and celite filtered, and then the mother liquor was slowly concentrated under reduced pressure and distilled under reduced pressure to obtain methyl 2-methyl-3-oxopentanoate.