Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH2:11])[CH3:8].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH:11][CH2:29][CH2:28][CH2:27][O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH3:8]
Reactant: CCCCC(CC)CN
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC(CC)CNCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 2-ethyl-n-hexylamine (0.35 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(2-ethyl-n-hexyl)-(3-(naphthalen-2-yloxy) propyl)amine solid, m.p. 97° C., (yield 0.6 gm, 84.8%).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][OH:10].[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23](OCC(Cl)(Cl)Cl)=[O:24])([CH3:13])[CH3:12]>C1COCC1>[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23]([O:10][CH2:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][N:3]=1)=[O:24])([CH3:13])[CH3:12]
Reactant: OCc1cnccn1
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1cnccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.4 %

Procedure:
NaH (0.22 g, 5.60 mmol, 60% dispersion in mineral oil) was suspended in THF (10 mL), cooled to 0° C. and pyrazin-2-yl methanol (0.49 mL, 5.00 mmol) was added. The suspension was stirred at 0° C. for 30 min and then added to a solution of Intermediate 2 (0.66 g, 2.00 mmol, 70% pure) in THF (10 mL) and the reaction mixture was stirred at room temperature. An additional such portion of NaH and pyrazin-2-yl methanol in THF was added after 18 h. After 2 d the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (10 mL) and the reaction mixture was stirred at room temperature for 2 h then concentrated in vacuo. The residue was dissolved in EtOAc (120 mL) and the organic layer was washed with 1 M aq Na2CO3 solution (6×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 0% to 100% (over 12 min) then 100% (over 3 min) MeOH in water (1% formic acid)). The residue was de-salted using K2CO3 in DCM to give pyrazin-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (62.9 mg, 10.4%) as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[S:17][C:16]2([CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:15][N:14]=1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>ClCCl>[CH3:12][C:13]1[S:17][C:16]2([CH2:22][CH2:21][N+:20]([O-:9])([CH3:23])[CH2:19][CH2:18]2)[CH2:15][N:14]=1
Reactant: CC1=NCC2(CCN(C)CC2)S1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Product: CC1=NCC2(CC[N+](C)([O-])CC2)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of m-chloroperbenzoic acid, mCPBA, (1.40 gr, 8.11 mmol) in dichloromethane (30 ml) was added gradually to a solution of AF150(S) (1.45 gr, 7.88 mmol) in dichloromethane (10 ml). The reaction was stirred at room temperature overnight Chromatography of the reaction mixture was on a column of natural aluminum oxide (Merck)(metanol:chloroform 1/49) gave AF406 (0.75 gr) as a crystalline solid. A sample was crystallized from ethylacetate. A very hygroscopic solid was obtained. mp. 130-132° C. (145-159° C. dec.); 1H NMR (300 MHz, CDCl3) δ 1.89 (m, 2H), 2.2 (t, j=1.5 Hz, CH3C═N), 2.82 (m, 2H), 3.24 (m, 2H), 3.25 (s, CH3N+O−), 3.35 (m, 2H), 4.03 (q, j=1.5 Hz, CH2N═C) ppm; IR(CHCl3) 2947, 1636, 1448, 1153, 931, 664 cm−1; MS(EI) 200 (M+), 184, 182, 149, 141, 140, 126, 110, 109, 108, 96, 82, 70.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[O:9].[CH3:10][O:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH2:16]Br)=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH2:16][N:3]2[CH:7]=[CH:6][CH:5]=[C:4]2[CH:8]=[O:9])=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=1
Reactant: COc1cc(CBr)c([N+](=O)[O-])cc1OC
Reactant: O=Cc1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Cn2cccc2C=O)c([N+](=O)[O-])cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a suspension of sodium hydride (0.724 g, 60% suspension in oil) in N,N-dimethylformamide (50 mL) was added pyrrole 2-carboxaldehyde (1.7 g, 18.1 mmol) and the reaction mixture was stirred for 30 minutes. It was then cooled to 0° C. and 4,5-dimethoxy-2-nitrobenzyl bromide (5.0 g, 1 equiv) was added dropwise over 20 minutes. After the addition, the reaction mixture was stirred at room temperature for 3 hours. It was then diluted with ethyl acetate (450 mL), washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was triturated with water, filtered and washed with water. This material was dried over anhydrous potassium carbonate in vacuo to provide the title compound as a yellow crystalline solid (4.97 g), m.p. 109-112° C., which was used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)=[O:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([O:5][C:6](=[O:27])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](=[O:18])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:41])([F:40])[F:28])=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(Br)cc2)cs1
Reactant: OB(O)Oc1ccc(C(F)(F)F)cc1
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: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Yield: 80.5 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(4-bromophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (600 mg) synthesized in Example 458-1 and 4-trifluoromethylphenylboric acid (363 mg) were dissolved in dioxane (8 mL) and 2M aqueous sodium carbonate solution (4 mL), tetrakis(triphenylphosphine)palladium (73 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (550 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].F[C:10]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH:13]=[CH:12][C:11]=1[N:21]1[C:26]2[CH:27]=[CH:28][O:29][C:25]=2[C:24](=[O:30])[C:23]([C:31]2[N:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:34]=[CH:33][CH:32]=2)=[N:22]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:36]1([N:35]2[C:31]([C:23]3[C:24](=[O:30])[C:25]4[O:29][CH:28]=[CH:27][C:26]=4[N:21]([C:11]4[CH:12]=[CH:13][C:14]([N:16]5[CH:20]=[CH:19][CH:18]=[N:17]5)=[CH:15][C:10]=4[O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[N:22]=3)=[CH:32][CH:33]=[N:34]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2F)c2ccoc12
Reactant: OCC(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2OCC(F)(F)F)c2ccoc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
To a solution of 2,2,2-trifluoroethanol (48 mg) in DMF (1 mL) was added 60% NaH (19.2 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, and 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)furo[3,2-c]pyridazin-4(1H)-one (70 mg) was added. The reaction mixture was stirred at 100° C. for 6 hr, and saturated aqueous sodium hydrogen carbonate solution was added. The reaction mixture was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (45 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)[C:3]=12.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C.O>[Si:27]([O:17][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[NH:8][N:9]=2)[CH:16]=[CH:15][CH:14]=1)([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncnc2[nH]nc(-c3cccc(O)c3)c12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2n[nH]c3ncnc(N)c23)c1
Reaction time: 16 h
Yield: 85.8 %

Procedure:
To a stirred solution of compound (2) (4.69 g, 20.66 mmol) and imidazole (2.10 g, 30.99 mmol) in dry DMF (100 mL) was added TBDMSCl (4.70 g, 30.99 mmol). After 16 hr, further aliquots of imidazole (2.10 g, 30.99 mmol) and TBDMSCl (4.70 g, 30.99 mmol) were added and the mixture was stirred for 48 hr. The reaction mixture was diluted with water (120 mL) and extracted with DCM (2×200 mL). The combined organic extracts were washed with water (2×200 mL), dried, filtered and the volume reduced to approximately 100 mL by evaporation in vacuo. The resulting slurry was filtered and the solid washed with heptane (50 mL) to afford the title compound (3) (6.05 g, 85%) as an off-white solid: m/z 343 (M+H)+ (ES+).
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:24][C@@H:25]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:40]2[C:45]([Cl:46])=[CH:44][N:43]=[C:42](Cl)[N:41]=2)(=[O:32])=[O:31])[CH2:26]1)(C)(C)C>>[Cl:46][C:45]1[C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[S:30]([N:27]2[CH2:28][CH2:29][C@@H:25]([OH:24])[CH2:26]2)(=[O:31])=[O:32])=[N:41][C:42]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:43][CH:44]=1
Reactant: COc1cc2c(cc1N)CCN(C[C@@H](C)O)CC2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@@H](O)C3)n1)CCN(C[C@@H](C)O)CC2
Yield: 29 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (R)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol and {2-[(R)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. The product was isolated as a white solid (35 mg, 29%). mp: 197-199° C., MS (ESI+): 603 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.58-7.52 (m, 2H), 7.25 (t, J=8 Hz, 1H), 6.66 (s, 1H), 4.37 (br s, 1H), 3.88 (m, 4H), 3.42 (m, 3H), 3.31 (d, 1H), 2.91-2.52 (m, 10H), 2.27 (m, 1H), 1.17 (d, J=6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)C1(NC(=O)c2ccc(CCl)cc2)CCCCC1
Product: COC(=O)C1(NC(=O)c2ccc(CN3CCOCC3)cc2)CCCCC1
Reaction time: 8 h
Yield: 83 %

Procedure:
30 ml of morpholine was added to 4 g (13 mmol) of 1-[[[4-(chloromethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid methyl ester, and the mixture was heated under reflux for 1 hour. The reaction solution was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration to obtain 3.8 g (83%) of the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].O=S(Cl)[Cl:20]>>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8]([Cl:20])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1
Temperature: 80 °C

Procedure:
3,5-Dihydroxybenzoic acid (7.2 g, 50 mM) was dissolved in 11 ml of acetic anhydride. To the resulting solution were added 5 drops of sulfuric acid, followed by stirring at room temperature for 20 minutes. Subsequently, 10 g of ice was added and 12 ml of 1N hydrochloric acid was then added. After sonication, a precipitated crystal was recovered by filtration. Washing the crystal with toluene gave 3,5-diacetoxybenzoic acid (10.23 g). The obtained 3,5-diacetoxybenzoic acid (2.38 g, 10 mM) was dissolved in 5 ml of SOCl2 and the solution was heated under reflux at 80° C. for 1 hour. The solvent SOCl2 was distilled off under reduced pressure to yield 3,5-diacetoxybenzoyl chloride (2.44 g).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][N:4]=1.[SH:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:9][C:8]1[C:3]([CH2:2][S:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
A mixture of 6.63 g of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine(30 mmol), 4.5 g of 2-mercaptobenzimidazol(30 mmol) and 8.67 g of triphenyl phosphine(33 mmol) was dissolved in 100 ml of tetrahydrofuran, 5.75 g of diethyl azodicarboxylate(DEAD)(33 mmol) dissolved in 30 ml of tetrahydrofuran was added dropwise thereto at room temperature, and stirred for 1 hour. The reaction mixture was concentrated under a reduced pressure, the resulting residue was combined with looml of ethylacetate, and extracted twice with 50 ml portions of 1N—HCl. The aqueous layer was then washed with 50 ml of diethylether; neutralized with 1N—NaOH to adjust the pH to 7. The resulting precipitates were filtrated, washed with water, and dried, to obtain 10.06 g of the title compound as a white solid(yield: 95%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([CH2:16][OH:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O.CCOCC>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([C:16]([OH:20])=[O:17])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1onc(-c2ccccc2)c1C(F)(F)F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(C)O
Product: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol (5.24 g, 21.6 mmol) in acetone (75 mL) at room temperature (immersed in a water bath) was added Jones' Reagent (43.8 mL, 53.9 mmol) via addition funnel slowly over 1.5 h. The dark reaction mixture was stirred at room temperature overnight. By HPLC, the reaction was 93% complete. An additional 0.5 equivalents (9 mL) of the Jones' Reagent was added. After 1 h, the reaction was 95% complete. After an additional 3h, the reaction was 96% complete. An additional 0.5 equivalents (9 mL) of the Jones' Reagent was added. The reaction mixture was stirred for an additional 2.5 h. By HPLC, the reaction was 97% complete. Isopropyl alcohol (6 mL) was added, and the mixture was stirred for 90 min, resulting in a dark green precipitate. The mixture was diluted with ether (600 mL), washed with a 2% aqueous solution of sodium hydrogen sulfite (5×100 mL), and the organic layer was collected. The aqueous layer was back-extracted with ether (2×100 mL). By HPLC, there was no additional product in the aqueous layer. The combined organic layers were washed with water (100 mL), washed with a saturated aqueous solution of brine (100 mL), and dried over anhydrous sodium sulfate. The aqueous layer was back-extracted with ether (100 mL), and the organic layer was added to the previous organic layers. The solution was concentration under reduced pressure to give 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid as an off-white solid. The solid was diluted with dichloromethane (200 mL), washed with a 2% aqueous solution of sodium hydrogen sulfite, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (3.84 g, 14.93 mmol, 69.3% yield) as a pale yellow solid. The product was 96% pure by HPLC with a ret. time=1.60 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=258.2.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([F:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][CH:14]([C:20]([CH3:22])=O)[C:15](OCC)=[O:16].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:22][C:20]1[C:14]([CH3:13])=[C:15]([OH:16])[C:10]2[C:8](=[C:7]([F:12])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=2)[N:9]=1
Reactant: CC(C)(C)c1ccc(N)c(F)c1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Yield: 23.4 %

Procedure:
4-t-Butyl-2-fluoroaniline (4.79 g) prepared according to the above process and ethyl 2-methyl-acetoacetate (4.96 g) were refluxed in toluene (60 ml) in the presence of trifluoroboron etherate (0.3 ml) for 3 hr to obtain a reaction solution. The reaction solution thus obtained was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The reaction product was refluxed in diphenyl ether (80 ml) for one hr and was allowed to stand for cooling. The precipitated product was then collected by filtration under the reduced pressure to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-hydroxyquinoline (compound 1, 1.66 g). 1H-NMR data on this compound in deutro-DMSO (dimethyl sulfoxide) were as shown below.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=O)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[S:42])=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccccc32)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=S)C2CCCc3ccccc32)cc1
Yield: 23.2 %

Procedure:
To a solution of N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.79 g) in toluene (10 mL) was added Lawesson's reagent (0.9 g), and the mixture was heated under reflux for 5 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carbothioamide (0.19 g). melting point: 123-125° C.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1)[C:5](=O)[CH3:6].[C:18]([CH2:20][C:21]([NH2:23])=[O:22])#[N:19].C[O-].[Na+]>CN(C)C=O>[CH3:6][C:5]1[NH:23][C:21](=[O:22])[C:20]([C:18]#[N:19])=[CH:3][C:4]=1[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1
Reactant: CC(=O)C(=CN(C)C)c1ccc2nccn2c1
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc2nccn2c1
Yield: 50.7 %

Procedure:
In 230 ml of N,N-dimethylformamide was dissolved 23.5 g of 4-dimethylamino-3-(imidazo[1,2-a]pyridin-6-yl)-3-buten-2-one. The solution was stirred at 80° to 90° C. for 12 hours, together with 9.48 g of α-cyanoacetamide and 12.2 g of sodium methoxide. After cooling, the solvnt was removed by distillation under reduced pressure and 500 ml of water was added to the residue to dissolve it. The solution was washed with 600 ml of chloroform. Next, about 5 ml of acetic acid was added to the aqueous layer to adjust pH to 6.5. Crystals precipitated upon cooling were taken by filtration. After the crystals were washed with water, acetonitrile and then ether, they were dissolved in 200 ml of a 2.5% aqueous sodium hydroxide solution. The solution was treated with activated charcoal. The filtrate was again adjusted to pH of 6.5 with about 7 ml of acetic acid. Crystals precipitated upon cooling were taken by filtration. After the crystals were washed with water, acetonitrile and then ether, they were recrystallized from 100 ml of N,N-dimethylformamide to obtain 13 g of 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridinecarbonitrile.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]2=[N:9][CH:8]=1)(C)C.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:6]([C:7]1[N:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]2=[N:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cnc2cnccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cnc2cnccn12
Reaction time: 1 h

Procedure:
To a solution of 3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyrazine (1.39 mol) in 10× volume of Ethyl acetate and 1.5× volume of Methanol is added two and a half equivalents of potassium carbonate at ambient temperature and the solution stirred for 1 hour. Potassium carbonate is filtered off and the organic stream is washed with water and with saturated sodium chloride solution (two or more times).