Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26]>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:26][CH2:25][C:24]([O:28][CH3:29])=[O:27])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (5.00 g, 0.021 mole) and triethylamine (0.5 ml) in methanol (50 ml) was added methyl acrylate (5.40 g, 0.063 mole). The mixture was stirred under argon at room temperature for about 20 hours. Volatiles were removed in vacuo to give an oil. Chromatography on silica gel and recrystallization from hexane gave the title compound, m.p. 63.5°-65.5°.
Reaction SMILES: [H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1([C:30](OCC)=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26].C1COCC1>CCOCC>[OH:31][CH2:30][C:20]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCCO1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C1(CO)CCCCO1
Temperature: 25 °C

Procedure:
A 1M solution of lithium tri-tert-butoxyaluminum hydride (8.79 mL, 8.79 mmol) was added dropwise to a cold (0° C.) stirred solution of diethyl tetrahydro-2H-pyran-2,2-dicarboxylate (0.810 g, 3.52 mmol) in an. THF (9 mL). After the addition is complete the mixture was allowed to warm to rt and heated to reflux for 4-5 h. The reaction mixture was cooled, diluted with ether and quenched with 20% NaHSO4 solution with vigorous stirring. The organic layer was separated, washed with brine and dried over MgSO4. The crude isolate was purified by silica gel FCC (5% MeOH in DCM) to afford ethyl 2-(hydroxymethyl)tetrahydro-2H-pyran-2-carboxylate as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.29 (q, J=7.0 Hz, 2H), 3.95-3.87 (m, 2H), 3.71 (dd, J=11.2, 8.2 Hz, 1H), 3.62 (dd, J=11.2, 5.1 Hz, 1H), 2.24-2.16 (m, J=8.0, 5.3 Hz, 1H), 2.14-2.06 (m, 1H), 1.84-1.72 (m, 1H), 1.64-1.50 (m, 4H), 1.37-1.29 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:14][C:13](=[O:15])[C:12]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH2:21]([O:15][C:13]1[C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[N:14]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(c2ccc(Br)cc2)=COc2ccc(F)cc21
Solvent: Cc1ccccc1
Product: Fc1ccc2c(c1)C(OCc1ccccc1)=NC(c1ccc(Br)cc1)=CO2
Temperature: 80 °C
Yield: 59.5 %

Procedure:
3-(4-Bromo-phenyl)-7-fluoro-4H-benzo[f][1,4]oxazepin-5-one (7.0 g, 0.021 mol) was dissolved in toluene (100 mL). Benzyl bromide (4.3 g, 0.025 mol) and Ag2CO3 (8.6 g, 0.031 mol) were added and the reaction mixture was heated at 80° C. until disappearance of the starting material. The solution was filtered through a pad of celite and concentrated to dryness. The crude was purified by flash chromatography on silica gel (n-hexane/EtOAc=7:1) to obtain the title compound (5.3 g, 60% yield) as a thick yellow oil.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][N:18]([CH3:33])[C:19]1[CH:20]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([N:18]([CH3:33])[CH3:17])[CH:20]=3)=[O:31])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC(F)(F)c1coc(Cn2ncc(N)n2)n1
Product: CN(C)c1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3nc(C(C)(F)F)co3)n2)c1

Procedure:
Following general procedure A, starting from 2-[4-(1,1-difluoro-ethyl)-oxazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-(dimethylamino)phenyl)oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[Na+:9].[Na+].C(O)(=O)CCC(O)=O.[S:19](=[O:23])(=[O:22])([OH:21])[OH:20].C(O)C.C([O-])(=O)CCC([O-])=O.[Na+].[Na+]>C(O)C>[C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[S:19]([O-:23])([O-:22])(=[O:21])=[O:20].[Na+:9].[Na+:9]
Reactant: O=C([O-])CCC(=O)[O-]
Reactant: O=S(=O)(O)O
Agent: O=C(O)CCC(=O)O
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)([O-])[O-]
Temperature: 30 °C

Procedure:
A mixture of 10.02 g of 200 proof ethanol and 0.502 g of 98% sodium succinate was prepared and heated to 30° C. These quantities allowed for a final solution of 10 wt % succinic acid in ethanol to be obtained upon acidification. The solubility of succinic acid in ethanol at 30° C. is about 12 wt %. Sulfuric acid (H2SO4) (0.338 g, 98%) was added to the ethanol/sodium succinate slurry with stirring to produce free succinic acid and sodium sulfate.
Reaction SMILES: C(N1CC[O:6][CH2:5][CH2:4]1)C.C(OC(=O)C)(=O)C.[CH2:16]([O:23][C:24](=[O:68])[C@H:25]([CH2:64][CH:65]([CH3:67])[CH3:66])[NH:26][C:27](=[O:63])[C@H:28]([C:59]([CH3:62])([CH3:61])[CH3:60])[NH:29][C:30](=[O:58])[C@H:31]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH3:57])[NH:32][C:33](=[O:49])[C@@H:34]([CH:46]([CH3:48])[CH3:47])[NH:35][C:36](=[O:45])[C@H:37]([CH2:39][O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH2:38])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)(O)[O-].[Na+]>ClCCl.[Cl-].[Na+].O>[CH2:16]([O:23][C:24](=[O:68])[C@H:25]([CH2:64][CH:65]([CH3:67])[CH3:66])[NH:26][C:27](=[O:63])[C@H:28]([C:59]([CH3:62])([CH3:61])[CH3:60])[NH:29][C:30](=[O:58])[C@H:31]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH3:57])[NH:32][C:33](=[O:49])[C@@H:34]([CH:46]([CH3:47])[CH3:48])[NH:35][C:36](=[O:45])[C@H:37]([CH2:39][O:40][C:41]([CH3:42])([CH3:44])[CH3:43])[NH:38][C:5](=[O:6])[CH3:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](NC(=O)[C@@H](N)COC(C)(C)C)C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Reactant: CCN1CCOCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](C(=O)N[C@@H](Cc1ccccc1C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5ml of N-ethylmorpholine and 0.37 ml of acetic anhydride were added in sequence to a solution of 1.95 g of N-[N-[N-[N-(O-tert-butyl-L-seryl)-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 70 ml of anhydrous dichloromethane. The mixture was stirred at room temperature for 1 hour and was then washedin sequence with 5% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine. The organic phase was dried overanhydrous magnesium sulphate and evaporated. Chromatography of the residue on silica using 5% methanol in dichloromethane for the elution gave afforded 1.45 g of N-[N-[N-[N-(N-acetyl-O-tert-butyl-L-seryl)-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester; MS: m/e 780.6 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]3)=[N:11][C:6]2=[CH:5][CH:4]=1.Cl>CCO>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)=[N:11][C:6]2=[CH:5][CH:4]=1
Reactant: COCCCn1c(C2CCCN(C(=O)OC(C)(C)C)C2)nc2ccc(OC)nc21
Agent: Cl
Solvent: CCO
Product: COCCCn1c(C2CCCNC2)nc2ccc(OC)nc21
Yield: 97 %

Procedure:
tert-Butyl 3-(5-methoxy-3-(3-methoxypropyl)-3H-imidazo[4, 5-13]pyridin-2-yl)piperidine-1-carboxylate (33C) (1.19 mmol; 0.481 g) was added to a 100 mL round-bottomed flask equipped with a reflux condenser and stirring under nitrogen. EtOH (15 mL) and HCl (8M in H2O; 4 mL) were then added and the solution was heated to reflux for 15 min. Analysis of the reaction mixture by LC/MS indicated that the reaction was complete at this time. The ethanol was then removed in-vacuo. The resultant solution was extracted with EtOAc and a 10% aqueous K2CO3 solution. The organic layer was collected and dried with Na2SO4. This was then filtered and concentrated and dried in-vacuo affording 5-Methoxy-3-(3-methoxypropyl)-2-(piperidin-3-yl)-3H-imidazo[4,5-b]pyridine (330) as a brown oil. (1.15 mmol, 0.351 g, 97% yield). ESI-MS: m/z 305.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH3:18])[CH2:5][CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.C(N(C(C)C)C(C)C)C>CO.O.CCOCC>[CH3:1][O:2][N:3]=[C:4]([CH3:18])[CH2:5][CH2:6][NH:7][C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2
Reactant: CON=C(C)CCN1C(=O)c2ccccc2C1=O
Reactant: Clc1ncnc2nc[nH]c12
Agent: NN
Solvent: CCOCC
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CON=C(C)CCNc1ncnc2nc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
0.282 g (1.00 mmol) of N-[3-(N-methoxyimino)butyl]phthalimide was dissolved in 6 ml of methanol and to the solution was added 60 μl (1.2 mmol) of hydrazine hydrate, followed by being refluxed for 7 hours. The reaction mixture was cooled to room temperature and then, 20 ml of ether was added thereto and the mixture was left to stand at 0° C. for 1 hour to sufficiently precipitate solids. The solids were removed by suction filtration and the filtrate was dried over sodium sulfate and concentrated to 1 ml by an evaporator. This concentrated filtrate was dissolved in 5 ml of isopropanol and to the solution were added 105 mg (0.680 mmol) of 6-chloropurine and 101 μl of ethyldiisopropylamine, followed by being refluxed on an oil bath for 5 hours. The reaction mixture was poured into 20 ml of water and extracted with chloroform (15 ml×5). The extract was dried over magnesium sulfate and the solvent was distilled off. The residue was purified by a thin layer chromatography (alumina, developing agent: 15% ethanol-chloroform) to give 85 mg (yield 35%) of the titled compound as white solids.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH2:6][CH:5]([S:8][C:9]2[CH:15]([CH3:16])[CH:14]3[N:11]([C:12](=[O:20])[CH:13]3[CH:17]([OH:19])[CH3:18])[C:10]=2[C:21]([OH:23])=[O:22])[CH2:4]1.[CH3:24][N:25]1[CH2:29][C:28](=O)[O:27]C1=O>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].O1CCOCC1>[OH:19][CH:17]([CH:13]1[C:12](=[O:20])[N:11]2[CH:14]1[C:15]([CH3:16])=[C:9]([S:8][CH:5]1[CH2:4][CH:3]([CH2:2][NH:1][C:28](=[O:27])[CH2:29][NH:25][CH3:24])[O:7][CH2:6]1)[CH:10]2[C:21]([OH:23])=[O:22])[CH3:18]
Reactant: CN1CC(=O)OC1=O
Reactant: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN)C3)C(C)C12
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNCC(=O)NCC1CC(SC2=C(C)C3C(C(C)O)C(=O)N3C2C(=O)O)CO1

Procedure:
The title compound is prepared by the procedure of Example 47 using 0.068 g of product from Example 46 in 2.0 ml of sodium phosphate buffer (pH 8.5) and 0. 029 g of 3-methyl -2,5-oxazolidinedione, prepared by the procedure described in J. Org. Chem., 34, No. 1, 243(1969), in 1 ml of dioxane to give 0.036 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C([Li])CCC.CN(C)[C:16](=[O:18])[CH3:17].[Cl-].[NH4+]>CCOCC.C(Cl)Cl.CO>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:16](=[O:18])[CH3:17])=[N:3][CH:4]=1
Reactant: CC(=O)N(C)C
Reactant: Cc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CC(=O)c1ccc(C)cn1
Temperature: -40 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 2-bromo-5-methylpyridine 49 (1.73 g, 10 mmol) in dry ether (20 ml), cooled to −78° C., was added n-butyllithium (6.25 ml of 1.6M solution in hexanes, 10 mmol, 1 equiv) dropwise. The reaction mixture was allowed to warm to −40° C. for 15 min, then cooled back to −78° C. again. N,N-dimethylacetamide (1.023 ml, 11 mmol, 1.1 equiv) was added dropwise and the mixture was stirred at −78° C. for 2 h. Saturated aqueous ammonium chloride (10 ml) was added and the organic layer was separated. The aqueous layer was extracted with ether (3×10 ml) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give an oily residue that was subjected to flash column chromatography using (5% methanol in methylene chloride) to give compound 51 (0.977 g, 72%) as a yellow oil: TLC Rf=0.48 (silica gel, 25% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.5-8.48 (m, 1H), 7.96-7.93 (d, 3J=8 Hz, 1H), 7.63-7.60 (m, 1H), 2.70 (s, 3H), 2.414 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 200.239, 151.741, 149.704, 137.786, 137.442, 121.663, 26.017, 18.969; HRMS calcd for C8H9NO+Na+ 158.0582; found 158.0580 [M+Na+].
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([C:26](=O)/[CH:27]=[C:28](\O)/[CH2:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:22]=[CH:23][C:24]=1[Cl:25]>C1COCC1.CCOC(C)=O>[Cl:18][C:19]1[CH:20]=[C:21]([C:26]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[C:28]([CH2:29][O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[CH:27]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: COc1ccc(NN)cc1
Reactant: O=C(/C=C(\O)COC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nc(COC3CCCCO3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C

Procedure:
4-Methoxyphenylhydrazine hydrochloride (3.88 kg, 21.8 mol) and K2CO3 (3.21 kg, 23.2 mol) were added to a THF/EtOAc solution containing (Z)-1-(3,4-dichlorophenyl)-3-hydroxy-4-[(tetrahydro-2H-pyran-2-yl)oxy]-2-buten-1-one (Example 514) at 0-10° C. The resultant suspension was stirred and allowed to warm to rt overnight (16 h). When HPLC analysis indicated the disappearance of the starting material, the reaction mixture was filtered. The organic reaction filtrate was washed with 1 M aq. citric acid (34.0 L), followed by 10% aq. NaCl (50.0 L) and the resulting product solution was used in the next synthetic step without isolation. HPLC (Method U): Rt=16.22 min. MS (ES+): mass calculated for C22H22Cl2N2O3, 432.10; m/z found, 455.1 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.39 (d, J=1.9 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.19 (dd, J=6.8, 2.2 Hz, 2H), 6.96 (dd, J=8.1, 2.1 Hz, 1H), 6.87 (dd, J=2.1, 7 Hz, 2H), 6.58 (s, 1H), 4.86 (d, J=12 Hz, 1H), 4.83-4.81 (m, 1H), 4.60 (d, J=12 Hz, 1H), 3.99-3.84 (m, 1H), 3.82 (s, 3H), 3.78-3.74 (m, 1H), 1.91-1.52 (m, 6H). 13C NMR (100 MHz, CDCl3): 159.5, 150.7, 141.8, 133.0, 132.7, 130.9, 130.8, 130.6, 128.1, 127.1, 114.7, 107.7, 98.6, 63.2, 62.6, 60.8, 55.9, 30.9, 25.8, 21.4, 19.7, 14.6.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:32]C)[CH:28]=2)[CH:23]=1.[Cl-].[Cl-].[Cl-].[Al+3].O>ClCCl>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([C:28]3[C:29]4[C:24](=[CH:23][C:22]([O:21][CH3:20])=[CH:31][CH:30]=4)[CH:25]=[CH:26][C:27]=3[OH:32])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc2cc(OC)ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(O)ccc2c1
Temperature: -5 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
Dissolve 4-(2-azepan-1-yl-ethoxy)-benzoyl chloride (79.4 g, 249 mmol) and 2,6-dimethoxynaphthalene (37.8 g, 201 mmol) in dichloromethane (800 ml). Cool to −5° C. and add aluminum trichloride (134 g, 1 mol). Warm to room temperature and stir overnight. Add chilled water (1.5 L) and stir vigorously for 1 hour. Decant the mixture away from the residue and separate organic. Wash the aqueous layer with dichloromethane (500 mL). Combine with residue from the reaction vessel and wash with saturated aqueous sodium bicarbonate (1 L). Separate the organic after prolonged stirring (2 hours) and wash the aqueous layer with dichloromethane (300 mL). Combine the organic layers and add Darco (30 g), silica gel (30 g), and magnesium sulfate. Filter and concentrate in vacuo to give 72.4 g of [4-(2-azepan-1-yl-ethoxy)-phenyl]-(2-hydroxy-6-methoxy-naphthalen-1-yl)-methanone (73%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1)[CH3:44]
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NC3(c4ccc(O)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)OC(C)(C)C)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-(4-(1-(4-hydroxyphenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (300 mg, 0.580 mmol) in DMF (Volume: 4 mL) was added ethyl 2-bromoacetate (0.067 mL, 0.609 mmol) and POTASSIUM CARBONATE (401 mg, 2.90 mmol). The mixture was at rt for 16 h. After cooling to rt, the mixture was diluted with EtOAc, washed with water, and brine. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography using 40% EtOAc/Hexanes to give tert-butyl 4-(4-(1-(4-(2-ethoxy-2-oxoethoxy)phenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (350 mg). LC-MS (Condition C), MS m/z (M++H) 576.4.
Reaction SMILES: C(O)(=O)C.[F:5][CH:6]([F:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1>[Fe].C(OCC)(=O)C>[F:5][CH:6]([F:16])[C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[NH2:13]
Reactant: O=[N+]([O-])c1cccc(C(F)F)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cccc(C(F)F)c1
Yield: 97.2 %

Procedure:
100 mg of Fe was added intio 3 ml of acetic acid and refluxed for 15 minutes. After lowering the temperature into room temperature, the mixture was added with 1-(difluoromethyl)-3-nitrobenzene (0.2 g, 1.15 mmol) and refluxed again for 1 hour. After addition of 20 ml ethyl acetate, impurities were removed using cellite and the organic layer was concentrated under vacuum. After column chromatography (ethylacetate/n-hexane, 1/15), the title compound (0.16 g, 50%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH2:11])=[O:10])=[N:7][CH:8]=1.[Na].C(S)C.[Cl:16][C:17]1[CH:24]=[CH:23][C:20](CCl)=[CH:19][CH:18]=1.ClC1C=CC(CCl)=CC=1.CN(C=O)C>CN(C=O)C.C(OCC)(=O)C>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:1][O:2][C:3]2[CH:4]=[CH:5][C:6]([C:9]([NH2:11])=[O:10])=[N:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(N)=O)nc1
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCS
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCc2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 5-methoxy-2-pyridylcarboxamide (2 g, 13.2 mmol) in 5 ml of DMF at RT is added the sodium salt of ethanethiol (26.3 mmol) in DMF (61.5 ml). The slurry is heated to 110° with stirring for about 15 minutes. The reaction is cooled to 50° and 40 ml of DMF is added. After 0.5 hour, the reaction is cooled to 10° & 4-chlorobenzyl chloride (2.47 g, 15.4 mmol) is added. The reaction is allowed to warm to RT and is stirred for 3 days. About 0.5 ml of 4-chlorobenzyl chloride/DMF (0.21 g/l ml) is added. After 2 hours at RT, the reaction is poured into ice water and ethyl acetate. The ethyl acetate is separated off, and the water layer is extracted with ethyl acetate (4X). The combined organic layers are washed with water and with brine, dried, filtered and rotoevaporated. The residue is washed with 20% ether/hexane (4X). The liquid is pipetted off and the residue is rotoevaporated to give 5-(4-chlorobenzyloxy)-2-pyridylcarboxamide.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)O1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27](I)=[CH:28][N:29]=2)[CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([C:9]3[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=3)=[CH:28][N:29]=2)[CH:26]=1
Reactant: Brc1ccc2ncc(I)n2c1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cnc3ccc(Br)cn23)cc1
Yield: 67.8 %

Procedure:
2.3 g methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate prepared according to T. Ishiyama et al., J. Org. Chem., 60, 7508 (1995), 2.0 g 6-bromo-3-iodoimidazo[1,2-a]pyridine (compound in Production Example 49), 2.5 g potassium phosphate, 360 mg tetrakistriphenyl phosphine palladium and 30 mL N,N-dimethylformamide were heated at 100° C. under nitrogen atmosphere. Insolubles were filtered off, the solvent was removed, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate to give 1.39 g of the title compound (colorless crystals).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C(OCl)(C)(C)C.[CH3:22][S:23][CH2:24][C:25](OCC)=[O:26].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:5]([C:4]1[CH:13]=[CH:14][CH:15]=[C:2]2[C:3]=1[CH:24]([S:23][CH3:22])[C:25](=[O:26])[NH:1]2)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)CSC
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1C(=O)Nc2cccc(C(=O)c3ccccc3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 30.6 (0.152 mole) of 3-aminobenzophenone in 160 ml. of methylene chloride was cooled to -78° C. in a dry ice/acetone bath and treated dropwise under a nitrogen atmosphere with a solution of 16.5 g. (0.152 mole) of t-butylhypochlorite in 60 ml. of methylene chloride. After stirring for 1 hr. after addition was complete, thin layer chromatography showed no starting material. A solution of 20.2 g. (0.152 mole) of ethyl α-(methylthio)acetate in 60 ml. of methylene chloride was added dropwise and stirring continued at -78° C. for 2.5 hr. A solution of 15.4 g. (0.152 mole) of triethylamine in 60 ml. of methylene chloride was added dropwise at -78° C. and the reaction mixture allowed to warm to room temperature while stirring for 16 hr. (overnight). The dark brown solution was treated with 100 ml. of 3N hydrochloric acid and stirred for 3 hrs. at room temperature. Precipitation of a tan solid began after 15-30 minutes. Filtration gave 18.5 g. of solid, m.p. 224°-228° C. (dec.) The layers of the filtrate were separated, the organic phase dried over magnesium sulfate, evaporated under reduced pressure, and the residue triturated in isopropyl ether (25 g.). The gummy solid was triturated in cold methanol to give 8.3 g. of product, m.p. 222°-225° C. (dec.). The total yield was 26.8 g. (62%). A 7.0 g. sample recrystallized from methanol weighed 5.6 g. and melted at 235°-237° C. (dec.).