Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5]1[C:6]([O:12][CH3:13])=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)(=O)C.C[O-:15].[Na+]>CO>[OH:15][CH2:11][C:8]1[CH:7]=[C:6]([O:12][CH3:13])[CH:5]=[CH:10][N:9]=1
Reactant: COc1cc(C)ncc1OC(C)=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(CO)c1
Yield: 41 %

Procedure:
Starting with 2-methyl-4-methoxypyridine-1-oxide (2.1 g) in the procedure of Part (ii) afforded 2.5 g of 2-acetoxymethyl-4-methoxypyridine which was contaminated with about 25% of 5-acetoxy-2-methyl-4-methoxypyridine. This mixture was dissolved in methanol (10 ml) containing 1.118 g (20.7 mmole) sodium methoxide and stirred at reflux for one hour. The methanol was evaporated in vacuo, the residue diluted with water, neutralized with dilute hydrochloric acid and extracted with chloroform. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give 853 mg (41%) 2-hydroxymethyl-4-methoxypyridine. 1H-NMR(CDCl3)ppm (delta): 3.9 (s, 3H), 4.72 (s, 2H), 5.35 (bs, 1H), 6.7 (dd, 1H), 6.95 (d, 1H), 8.3 (d, 1H).
Reaction SMILES: ClC1C(OC)=CC=C(Cl)C=1NC(=O)[N:13]([CH3:34])[C:14]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24](N3CCN(C)CC3)=[CH:23][CH:22]=2)[N:17]=[CH:16][N:15]=1.[CH3:36][N:37]([CH2:39]C1C=C(N)C=CC=1)[CH3:38].Cl>O1CCOCC1>[CH3:36][N:37]([CH2:39][C:25]1[CH:26]=[C:21]([NH:20][C:18]2[CH:19]=[C:14]([NH:13][CH3:34])[N:15]=[CH:16][N:17]=2)[CH:22]=[CH:23][CH:24]=1)[CH3:38]
Reactant: CN(C)Cc1cccc(N)c1
Reactant: COc1ccc(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(N4CCN(C)CC4)cc3)ncn2)c1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CNc1cc(Nc2cccc(CN(C)C)c2)ncn1
Temperature: 150 °C
Yield: 59.8 %

Procedure:
A mixture of (6-chloro-pyrimidin-4-yl)-methyl-amine (Example 1) (750 mg, 5.2 mmol), 3-dimethylaminomethyl-phenylamine (787 mg, 5.2 mmol) and 4N HCl in dioxane (15 ml) is heated in a sealed tube to 150° C. for 5 h. The reaction mixture is concentrated, diluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH+1% NH3aq, 9:1) affords 800 mg of the title compound as a white solid: ESI-MS: 258.1 [MH]+; tR=1.00 min (purity: 100%, gradient J); TLC: Rf=0.14 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](=[O:9])[CH3:8].[CH3:10][O:11][N:12]=[C:13]1[C:21]2[C:16](=[CH:17][C:18](B(O)O)=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][O:11][N:12]=[C:13]1[C:21]2[C:16](=[CH:17][C:18]([C:2]3[CH:6]=[CH:5][O:4][C:3]=3[C:7](=[O:9])[CH3:8])=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CON=C1CCc2cc(B(O)O)ccc21
Reactant: CC(=O)c1occc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CON=C1CCc2cc(-c3ccoc3C(C)=O)ccc21
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 1-(3-bromofuran-2-yl)ethanone (A. Tanaka et al., J. Heterocycl. Chem., 1995, 32, 4 1289) (2.5 g, 13.2 mmol), the product of Example 5 Step 6 (2.83 g, 13.9 mmol), sodium carbonate (2.8 g, 27.7 mmol) in toluene (40 ml) and water (14 ml) was treated with triphenylphosphine (0.35 g, 1.3 mmol) and palladium acetate (150 mg, 0.66 mmol) and heated under reflux for 18 hours. After cooling to room temperature, the mixture was filtered through celite and the filtrate diluted with water and ethyl acetate. The organic phase was separated, washed with water and saturated brine, dried (MgSO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with a mixture of diethyl ether/dichloromethane (5:95) to afford the title compound (2.5 g, 70%); MS(ES+) m/e 270 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:10]([I:11])=[C:6]2[N:5]=[C:4]([CH3:19])[N:3]=1.C(N(CC)CC)C.[CH2:27]([NH:29][C:30]1([C:36]([NH2:38])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:28]>O1CCCC1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[C:10]([I:11])=[C:6]2[N:5]=[C:4]([CH3:19])[N:3]=[C:2]([N:33]3[CH2:32][CH2:31][C:30]([NH:29][CH2:27][CH3:28])([C:36]([NH2:38])=[O:37])[CH2:35][CH2:34]3)[N:7]2[N:8]=1
Reactant: CCNC1(C(N)=O)CCNCC1
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(I)c2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC1(C(N)=O)CCN(c2nc(C)nc3c(I)c(-c4ccccc4Cl)nn23)CC1
Reaction time: 8 h
Yield: 134.2 %

Procedure:
To a solution of 4-chloro-7-(2-chlorophenyl)-8-iodo-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-1A-1e; 28 mg, 0.069 mmol) and triethylamine (14 μl, 0.10 mmol) in tetrahydrofuran (1 ml) was added 4-ethylaminopiperidine-4-carboxylic acid amide (I-1A-1h; 13 mg, 0.076 mmol) and the mixture was stirred overnight. The mixture was extracted from water with ethyl acetate, the combined organic layers were washed with brine, dried (MgSO4), filtered through a 0.45 μm filter disk, and then concentrated, in vacuo, to afford the crude product (50 mg). Purification on a Chromatotron using 0-20-30% acetonitrile in methylene chloride as eluant afforded product I-1A-1i (20 mg, 54%): +APcI MS (M+1) 540.8; 1H NMR (400 MHz, CD2Cl2) δ 7.54 (d, J=7.9 Hz, 1H), 7.47-7.38 (m, 3H), 4.83-4.65 (br m, 2H), 4.20-4.05 (br m, 2H), 2.55 (q, J=7.1 Hz, 2H), 2.50 (s, 3H), 2.26-1.98 (m, 2H), 1.78-1.75 (m, 2H), 1.10 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(#N)C>[CH2:18]([O:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Yield: 103.2 %

Procedure:
To 2-nitro-5-fluorophenol (6.28 g) in acetonitrile (50 ml) was added potassium carbonate (5.6 g) and benzyl bromide (7.2 g). The mixture was stirred at reflux for 2 hrs, added to water and extracted with diethyl ether. The organic layer was washed with brine, dried and evaporated to dryness to give 2-(benzyloxy)-4-fluoro-nitrobenzene (10.2 g) as a solid. nmr (deuterochloroform): 5.2d (s), 2H; 6.7d, (m), 1H; 6.8d (q), 1H; 7.4d (m), 5H; 8.0d, (q), 1H;
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:22][CH2:21]4)[CH:19]=3)=[C:11](N)[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2].C(N1C2C(=CC(C3C=CC(S(C)(=O)=O)=CC=3)=C([F:43])C=2)N(C(OC(C)C)=O)C[C@@H]1C)(=O)C>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:22][CH2:21]4)[CH:19]=3)=[C:11]([F:43])[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(F)c(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Product: CC(=O)N1c2cc(F)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C

Procedure:
Isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-6-fluoro-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized from isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1 (2H)-carboxylate according to the procedure described above for isopropyl (S)-4-acetyl-6-fluoro-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 241). MS (ESI, pos. ion) m/z 401 [M+H]+.
Reaction SMILES: [C:1]1([C@@H:7]2[C@@H:16]3[CH2:17][CH2:18][NH:19][C@@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([NH:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[C:35](O)=[O:36])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1.C(#N)C>[C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:35]([C@H:30]4[CH2:31][CH2:32][CH2:33][CH2:34][C@H:29]4[NH:28][C:20](=[O:27])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:36])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc([C@H]2Nc3ccccc3[C@H]3NCC[C@@H]23)cc1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)O)c1ccccc1
Agent: CCOC(=O)OC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21)c1ccccc1
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a mixture of (3aR*,4S*,9bS*)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (620 mg, 2.47 mmol), (1S,2R)-2-(benzoylamino)cyclohexanecarboxylic acid (671 mg, 2.7% mmol), triethylamine (0.72 ml, 5.2 mmol), acetonitrile (17 ml) and tetrahydrofuran (17 ml) was added dropwise DEPC (440 mg, 2.7 mmol) under ice-cooling, and the mixture was stirred for 10 min. The mixture was allowed to return to room temperature and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried (over anhydrous Na2SO4), and the solvent was evaporated. The residue was subjected to column chromatography using silica gel (30 g), and eluted with hexane-ethyl acetate (9:1-7:3, v/v) to give the title compound (735 mg, 62%) as an amorphous form.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:13]=[N:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]([CH3:11])[CH2:8][C@H:7]([CH3:12])[CH2:6]1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:16]([O:15][N:14]=[CH:13][C:5]1([C:3]([OH:4])=[O:2])[CH2:10][C@H:9]([CH3:11])[CH2:8][C@H:7]([CH3:12])[CH2:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)C1(C=NOCc2ccccc2)C[C@H](C)C[C@H](C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1C[C@H](C)CC(C=NOCc2ccccc2)(C(=O)O)C1
Temperature: 90 °C

Procedure:
A mixture of (3S,5R)-1-(benzyloxyimino-methyl)-3,5-dimethyl-cyclohexanecarboxylic acid methyl ester (4.8 g, 15.8 mmol) and lithium hydroxide monohydrate (6.6 g, 158 mmol) in THF (170 mL) and water (85 mL) was heated at 90° C. for 48 h. The reaction mixture was acidified to pH 3 with 6N aqueous HCl and was extracted with dichloromethane (75 mL×6). The combined organic layers were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a pale yellow oil. (1.8 g, 39%). MH+290.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[S:8][C:9]2[CH:21]=[C:20]([O:22]C)[CH:19]=[CH:18][C:10]=2[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[S:8][C:9]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:10]=2[C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:6]
Reactant: COc1ccc2c(-c3ccccc3)c(C(=O)c3cccc(Cl)c3)sc2c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1cccc(Cl)c1)c1sc2cc(O)ccc2c1-c1ccccc1
Temperature: 0 °C
Yield: 39 %

Procedure:
A mixture of 10.9 g. of the product from Example 16 and 33.6 g. of pyridine hydrochloride was refluxed in a 220° C. oil bath for 1.5 hours. The hot reaction mixture then was poured over an ice-water mixture, and the resulting solid was collected. The solid was washed with water and dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The ethyl acetate solution then was filtered and evaporated. The residue was recrystallized from a mixture of methanol and a minimum of acetone to give 5.07 g. (39 percent) of the title compound, m.p. 215° C.
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O-])([O-])=O.[Cs+].[Cs+].CI.O>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccnc1I
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1cccnc1I
Reaction time: 1 h

Procedure:
To a solution of 2-iodopyridin-3-ol (45.3 mg, 0.205 mmol) in DMF (3 mL) was added Cs2CO3 (334 mg, 1.030 mmol) and MeI (25 μL, 0.410 mmol). After 1 hour, the reaction was poured into water (10 mL), diluted with EtOAc (20 mL), washed with water (3×10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-iodo-3-methoxypyridine. LCMS=236.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 8.00 (dd, J=1.4, 4.6 Hz, 1H), 7.20 (dd, J=4.6, 8.0 Hz, 1H), 7.00 (dd, 1.4, 8.3 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:7][N:6]1[C:2]([N:14]2[CH2:15][CH2:16][CH2:17][O:11][CH2:12][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: C1CNCCOC1
Product: Cn1ncc([N+](=O)[O-])c1N1CCCOCC1
Yield: 52 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 1,4-oxazepane gave 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-oxazepane as a yellow oil (72 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 3.94 (t, J=5.6 Hz, 2H), 3.88-3.84 (m, 2H), 3.80 (s, 3H), 3.40-3.35 (m, 4H), 2.07-1.99 (m, 2H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:7]=[CH:6][C:5]2=1.[OH-].[Na+].Cl[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1.Cl>O.CS(C)=O>[CH3:19][CH:15]([C:8]1[CH:7]=[CH:6][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([O:1][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH:3]=3)[N:11]([CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[C:10]=2[CH:9]=1)[C:16]([OH:18])=[O:17]
Reactant: CC(C(=O)O)c1ccc2c(c1)[nH]c1ccc(O)cc12
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C(=O)O)c1ccc2c3cc(OCc4ccc5ccccc5n4)ccc3n(Cc3ccc4ccccc4n3)c2c1

Procedure:
A mixture consisting of 6-hydroxy-α-methyl carbazole-2-acetic acid (2.6 g, 0.010 mol), dimethyl sulfoxide (200 mL), sodium hydroxide (2.0 g in 20 mL H2O, 0.05 mol) and 2-chloromethylquinoline.HCl (4.0 g, 0.018 mol) is heated to 80° C. for 3 hours. The reaction mixture is cooled, poured into water (1000 mL), and the pH is adjusted to 4 with 1N HCl. The aqueous solution is extracted with ethyl acetate (4×300 mL) and the organic layers are combined, washed with water (2×300 mL), once with brine (300 mL), dried over MgSO4, filtered and concentrated to give 3.0 g of crude product. The latter is chromatographed on silica gel using 10% methanol/methylene chloride as an eluent to give 8 g of product, m.p. 197°-199° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:6])=[O:5])[CH3:2].[CH2:11]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14]O)[CH3:12]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].O>[CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([O:6][CH2:14][CH:13]([CH2:11][CH3:12])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCCCC(CC)CO
Reactant: CCCCC(CC)C(=O)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Product: CCCCC(CC)COC(=O)C(CC)CCCC
Reaction time: 9 h
Yield: 95.9 %

Procedure:
144 g (1 mol) of 2-ethylhexanoic acid and 143 g (1.1 mol) of 2-ethylhexanol were fed to a four-necked flask equipped with a stirrer, a thermometer and a water separator having a condenser tube, and the mixture was heated to 200° C. under reduced pressure in the presence of a tetraisopropyl titanate catalyst. Esterification reaction was carried out for about 9 hours while removing the formed water by the water separator. After the reaction, the excess 2-ethylhexanol was distilled off, and the product was neutralized with excess sodium hydroxide and then washed with water to neutrality. The product was then treated with activated carbon (0.3 wt. % relative to the starting materials fed) at 90° C., and was then filtered, giving 246 g of (2-ethylhexyl) 2-ethylhexanoate, which was then dehydrated for 5 hours at a temperature of 100° C. and a reduced pressure of 13.3 MPa. The resulting ester had a total acid number of 0.01 mgKOH/g, a water content of 11 ppm, a kinematic viscosity of 2.7 mm2/s (40° C.) and 1.1 mm2/s (100° C.), a volume resistivity of 3.0×1013 Ω·cm, and a two-layer separation temperature of −24° C.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:11][N:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[N:14][C:9]([O:8][CH2:7][C:6]([OH:22])=[O:5])=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)COc1ncc(-c2ccccc2F)cn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ncc(-c2ccccc2F)cn1
Reaction time: 3 h

Procedure:
335 mg (1.1 mmol) of [5-(2-fluoro-phenyl)-pyrimidin-2-yloxy]-acetic acid tert-butyl ester in 10 ml of 90% aqueous TFA were allowed to stand at room temperature for 3 h. After evaporation, a sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The aqueous phase was acidified to pH=4, extracted with ethyl acetate, and the combined organic phases were dried and evaporated. Yield: 51 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:16])[C:10](=[CH2:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([NH:31][CH2:15][CH:10]([CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[OH:16])[C:11]([O:13][CH3:14])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: C=C(C(=O)OC)C(O)c1ccc(Cl)c(Cl)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 2-[(3,4-dichlorophenyl)(hydroxy)methyl]prop-2-enoate (13.6 g) and triethylamine (8.74 ml) in methanol (100 mL) was added benzylamine (6.84 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (12.7 g).
Reaction SMILES: [OH:1][CH:2]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:3][NH:4][CH:5]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[C:14](=[O:20])[C:15](=[O:19])[C:16]=2OC)[CH:9]=[CH:10][CH:11]=1.[NH3:35]>C(O)C>[NH2:35][C:16]1[C:15](=[O:19])[C:14](=[O:20])[C:13]=1[NH:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:5]([NH:4][CH2:3][CH:2]([OH:1])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH:7]=1
Reactant: COc1ccc(C(NCC(O)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Reactant: N
Solvent: CCO
Product: COc1ccc(C(NCC(O)c2ccccc2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1d), 3-{3-[(2-hydroxy-2-phenylethylamino)-(4-methoxyphenyl)methyl]phenylamino}-4-methoxy-3-cyclobutene-1,2-dione (1.35 g) [prepared as described in step (d) above] and a solution of ammonia in ethanol (2N, 19 ml) were reacted, to give the title compound (1.36 g) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][NH:6]N.[CH2:8]([O:10][C:11](=[O:19])[C:12](=O)[CH:13]=[CH:14][N:15](C)C)[CH3:9]>C(O)C>[CH2:8]([O:10][C:11]([C:12]1[N:6]([CH2:5][CH2:4][O:3][CH3:2])[N:15]=[CH:14][CH:13]=1)=[O:19])[CH3:9]
Reactant: CCOC(=O)C(=O)C=CN(C)C
Reactant: COCCNN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccnn1CCOC
Temperature: 60 °C

Procedure:
2-Methoxyethylhydrazine hydrochloride (Ref: J. Med. Chem. (1967) 11 (1) 79-83) (1.07 g, 8.5 mmol) and ethyl-4-dimethylamino-2-oxo-but-3-enoate (1.5 g, 8.5 mmol) were dissolved in ethanol (10 ml) and heated at 60° C. for 7 hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (80 ml) and dilute sodium carbonate solution (40 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent removed in vacuo to give a brown gum. This material was chromatographed on silica gel (30 g) using 40% to 20% heptane in ethyl acetate. The higher running product was collected to give 2-(2-methoxyethyl)-2H-pyrazole-3-carboxylic acid ethyl ester as 750 mg of a mobile yellow oil. The lower running product was collected to give 1-(2-methoxyethyl)-1H-pyrazole-3-carboxylic acid ethyl ester as 360 mg of a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:19])[CH:15]2[CH2:18][O:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][N:14]([CH:15]1[CH2:16][O:17][CH2:18]1)[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1COC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C1CCNCC1)C1COC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(methyl(oxetan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.55 mmol) and TFA (4 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording Methyl(oxetan-3-yl)piperidin-4-ylamine as a white solid (94 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 4.67 (t, J=6.7 Hz, 2 H); 4.61 (t, J=6.7 Hz, 2 H); 3.97 (p, J=6.7 Hz, 1 H); 3.14 (d, J=12.3 Hz, 2 H); 2.56 (td, J=12.2, 4.0 Hz, 2 H); 2.48-2.26 (m, 2 H); 2.22 (s, 3 H); 1.63 (d, J=12.3 Hz, 2 H); 1.40 (qd, J=12.2, 4.0 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][CH2:8][C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[CH2:21])=[C:15]([OH:22])[C:12]=3[C:13]=2[CH3:14])=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[C:15]([OH:22])[C:12]=3[C:13]=2[CH3:14])=[CH:23][CH:24]=1
Reactant: C=CCc1ccc2oc(CCc3ccc(OC)cc3)c(C)c2c1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc2oc(CCc3ccc(OC)cc3)c(C)c2c1O

Procedure:
A solution of 2-(p-methoxyphenethyl)-3-methyl-4-hydroxy-5-allylbenzofuran (0.65 gm, 2 mmoles) in ethanol (50 mL) was hydrogenated in a Parr hydrogenator in the presence of 5% palladium on charcoal at 50 psi for a period of 2 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo to yield 2-(p-methoxyphenethyl) 3-methyl-4-hydroxy-5-propylbenzofuran, mp 77°-79° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cncc(Br)c1
Product: Brc1cncc(-c2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and phenylboronic acid.