Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].F[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1.O>CS(C)=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N+:10]([O-:12])=[O:11])=[N:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(Cl)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Cl)cn1
Temperature: 20 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
9.9 g potassium hydroxide powder and 5.0 g 1-fluoro-2-nitrobenzene were added little by little in this order to a solution of 5.8 g 5-chloro-2-aminopyridine in dimethyl sulfoxide (100 mL), and the mixture was stirred at 20° C. for 4 hours under nitrogen atmosphere. The reaction solution was poured into iced water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane, to give 6.02 g of the title compound as orange crystals.
Reaction SMILES: C[Si](N[Si](C)(C)C)(C)C.[Li]CCCC.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=O)=[CH:18][CH:17]=1.[CH2:30]([O:32][C:33](=[O:39])[CH2:34][Si](C)(C)C)[CH3:31]>C1COCC1>[OH:15][C:16]1[CH:21]=[CH:20][C:19](/[C:22](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:34]\[C:33]([O:32][CH2:30][CH3:31])=[O:39])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(/c1ccccc1)c1ccc(O)cc1
Reaction time: 0.75 h
Yield: 55.9 %

Procedure:
To a solution of HMDS (21.17 g, 131.1 mmol) in THF (200 mL) was cooled to −40° C. Then it was added with n-BuLi (56.7 mL, 136.22 mmol) and stirred at same temperature for 45 min. After that (4-hydroxyphenyl)(phenyl)methanone (2 g, 10 mmol) in THF was added slowly over a period of 10 min and stirred at −40° C. to −30° C. for one hour. Then Ethyl(trimethylsilyl)acetate (2.42 g, 15.1 mmol) was added drop wise and stirred at 0° C. to 15° C. for completion of starting material (4 h). After reaction completed reaction was quenched with ammonium chloride and then THF was evaporated under vacuum and the resulted solution was partitioned between water and Ethyl acetate. The combined organic layer was dried and evaporated to get crude. The crude was purified through chromatography and triturated with n-Hexane to afford red color oil as product (1.5 g, Yield: 55.9%); 1H NMR (300 MHz, CDCl3): δ 7.31-7.33 (m, 4H), 7.01-7.74 (d, 1H), 6.7-7.16 (m, 4H), 6.25 (s, 1H), 3.94-3.99 (q, 2H), 1.07-1.10 (t, 3H)
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][NH:5][C:6]([C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)=[O:7].O.O[Li].O.Cl>C1COCC1>[CH3:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:21])=[O:2])=[O:7])[CH:13]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)CNC(=O)c1cc(-c2ccc(C)cc2)ccn1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2ccnc(C(=O)NCC(=O)O)c2)cc1
Reaction time: 16 h
Yield: 12 %

Procedure:
To a solution of [(4-(4-methyl-phenyl)pyridine-2-carbonyl)-amino]-acetic acid methyl ester, 24, (0.092 g, 0.32 mmol) in THF (2 mL) at room temperature is added H2O (1 mL) and LiOH.H2O (0.027 g, 0.64 mmol). The reaction is stirred for 16 hours after which time the solution is acidified using 1M HCl. The solvents are removed under reduced pressure and the solid that remains is suspended in a mixture of THF: MeOH and filtered. The filtrate is concentrated under reduced pressure and the resulting solid is triturated with MeOH and collected by filtration to provide 0.012 g (12% yield) of the desired compound as a colorless solid. 1H NMR (250 MHz, MeOD) δ ppm 8.69 (1H, d, J=4.8 Hz), 8.38 (1H, s), 7.86 (1H, d, J=6.2 Hz), 7.72 (2H, d, J=8.1 Hz), 7.38 (1H, d, J=7.9 Hz), 8.38 (1H, s), 2.44 (2H, s). HPLC-MS: m/z 271 [M+H]+.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH2:9]([O:11][C:12](=[O:28])[CH:13]=[CH:14][C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)[CH3:10]>CS(C)=O>[CH2:9]([O:11][C:12]([C@@H:13]1[CH2:2][C@H:14]1[C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)=[O:28])[CH3:10]
Reactant: CCOC(=O)C=Cc1ccc(-c2ccc(F)cc2)nc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
100 ml of dry dimethyl sulfoxide were added slowly to a mixture of 9.30 g (42.3 mmol) of trimethylsulfoxonium iodide and 976 mg (40.1 mmol) of sodium hydride. The mixture was stirred at room temperature for 15 min, and then 8.5 g (31.3 mmol) of 3-[6-(4-fluoro-phenyl)-pyridin-3-yl]-acrylic acid ethyl ester were added. The reaction mixture was stirred at room temperature for 18 h and then poured onto ice/water and extracted with ethyl acetate. The combined organic phases were dried and evaporated. The obtained raw product was purified by column chromatography (silica gel, dichloromethane). Yield: 6.75 g.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[Na].[CH:23]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([O:29][C:2]2[C:10]3[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=3[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=2[C:18]([F:21])([F:20])[F:19])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Reactant: OC1CCCCC1
Agent: [Na]
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(OC2CCCCC2)c2[nH]c(C(F)(F)F)nc12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with the sodium sale of cyclohexanol to obtain 4-cyclohexyloxy-7-nitro-2,5-bis(trifluoromethyl)benzimidazole, m.w., 397.3.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C@@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])=[O:22])=[CH:17][CH:16]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: O=C(c1ccc(Cl)cc1)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(C(=O)N2CCC[C@H]2C(=O)c2ccc(Cl)cc2)c(C(F)F)n1
Reaction time: 3 h
Yield: 97.3 %

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (1.94 g; 10.0 mmol) in dichloromethane (5 ml) was added dropwise to a stirred suspension of (4-chloro-phenyl)-(S)-pyrrolidin-2-yl-methanone hydrochloride (2.46 g; 10.0 mmol), which was prepared as described in example P16, and triethylamine (3.0 g; 30.0 mmol) in dichloromethane (25 ml). Dichloromethane (40 ml) was added to the mixture. The ice bath was removed and reaction mixture was allowed stirring for 3 hours. The reaction mixture was washed with 1M NaOH (20 ml), 1M HCl (20 ml) and saturated NaCl (20 ml) and then dried over Na2SO4. After removal of the solvent, the residue was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:19). 3.58 g (97.3% of theory) of (4-chloro-phenyl)-[(S)-1-(3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl)-pyrrolidin-2-yl]-methanone was obtained in form of an oil. 1H NMR (400 MHz, CDCl3): δ 1.91-1.98 (m, 1H), 2.02-2.16 (m, 2H), 2.33-2.42 (m, 1H), 3.75-3.85 (m, 2H), 3.97 (s, 3H, NCH3), 5.61-5.65 (m, 1H), 6.99-7.28 (t, 1H, CHF2), 7.45-7.47 (d, 2H, Ar—H), 7.73 (s, 1H) 7.96-7.98 (d, 2H, Ar—H). MS [M+H]+ 368/370.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([N:16]1[C:24]3[CH:23]=[C:22]([N+:25]([O-])=O)[C:21]4[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=4[C:19]=3[CH:18]([CH2:32][Cl:33])[CH2:17]1)=[O:15])=[CH:8]2)(=[O:3])[CH3:2]>C1COCC1.O=[Pt]=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([N:16]1[C:24]3[CH:23]=[C:22]([NH2:25])[C:21]4[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=4[C:19]=3[CH:18]([CH2:32][Cl:33])[CH2:17]1)=[O:15])=[CH:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3ccccc43)cc2c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(N)c3ccccc43)cc2c1
Yield: 88 %

Procedure:
A solution of 14c (170 mg, 0.37 mmol) in THF (60 mL) was hydrogenated over PtO2 at 50 psi for 2 h. After removal of the catalyst, the solution was concentrated to a small volume under reduced pressure below 25° C. and diluted with EtOAc/iPr2O to give 15c (141 mg, 89%). mp >300° C. 1H NMR [(CD3)2SO] δ 11.61 (d, J=1.4 Hz, 1 H, indole NH), 9.84 (s, 1 H, NHCO), 8.08 (d, J=8.5 Hz, 1 H, H-6), 8.05 (d, J=1.4 Hz, 1 H, H-4'), 7.76 (d, J=8.2 Hz, 1 H, H-9), 7.71 (s, 1 H, H-4), 7.46 (t, J=7.5 Hz, 1 H, H-8), 7.42 (d, J=8.9 Hz, 1 H, H-7'), 7.33 (dd, J=8.8, 1.9 Hz, 1 H, H-6'), 7.29 (t, J=7.5 Hz, 1 H, H-7), 7.14 (d, J=1.7 Hz, 1 H, H-3'), 5.98 (s, 2 H, NH2), 4.74 (dd, J=10.8, 9.0 Hz, 1 H, H-2), 4.51 (dd, J=11.0, 1.6 Hz, 1 H, H-2), 4.17-4.08 (m, 1 H, H-1), 3.97 (dd, J=11.0, 3.0 Hz, 1 H, CHHCl), 3.77 (dd, J=10.9, 7.8 Hz, 1 H, CHHCl), 2.06 (s, 3 H, CH3).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([OH:20])=O)=[CH:10][CH:9]=1)(=[O:7])[CH3:6]>C1(C)C=CC=CC=1>[C:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([Cl:3])=[O:20])=[CH:10][CH:9]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)c1ccc(C(=O)O)c2ccccc12
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C(=O)Cl)c2ccccc12
Temperature: 90 °C
Yield: 98.7 %

Procedure:
Thionyl chloride (35.00 g, 0.29 mol) was added to 4-acetyl-1-naphthalenecarboxylic acid (51.70 g, 0.24 mol) in toluene (350 mL). The mixture was warmed to 90° C. for 8.5 h. After cooling to 25° C., the solvent was removed under reduced pressure to give the title product as an off-white solid (55.1 g, 98.7% yield).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (120 mg, 0.36 mmol) in DCM (6 ml), were sequentially added triethylamine (79 μl, 1.08 mmol) and methanesulfonyl chloride (33.4 μl, 0.43 mmol). The reaction was stirred at RT for 3 hours, and then the volatiles were evaporated. The crude was taken up with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude was triturated with Et2O to obtain (R)-quinuclidin-3-yl 2-(methylsulfonamido)-2-phenylacetate (38.9 mg; 32% yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20]S(C)(=O)=O)([CH3:18])[CH2:13]1.C([O-])([O-])=O.[K+].[K+].[CH2:31](O)[C:32]([F:35])([F:34])[F:33]>O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:18])([CH2:19][O:20][CH2:31][C:32]([F:35])([F:34])[F:33])[CH2:13]1
Reactant: CC1(COS(C)(=O)=O)CCCN(CC2COc3ccccc3O2)C1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(COCC(F)(F)F)CCCN(CC2COc3ccccc3O2)C1

Procedure:
A mixture of methanesulfonic acid 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethyl ester (0.35 g, 0.98 mmol), K2CO3 (0.68 g) and trifluoroethanol (4 ml) was irradiated in a microwave reactor at 150° C. for 10 min. Water was added and the reaction mixture was extracted with DCM (2×20 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 90:10).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:41][C@:42]([CH3:48])([CH:45]([CH3:47])[CH3:46])[CH2:43][OH:44].CCN(C(C)C)C(C)C>C(#N)C>[OH:44][CH2:43][C@@:42]([NH:41][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:48])[CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)[C@@](C)(N)CO
Reactant: O=C(O)c1cc(OCC2CCC2)c(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)[C@](C)(CO)NC(=O)c1cc(OCC2CCC2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-4-cyclobutylmethoxy-pyridine-2-carboxylic acid (60 mg, 249 μmol) in acetonitrile (2 mL) was added HATU (123 mg, 324 μmol), (2R)-2-amino-2,3-dimethyl-1-butanol (CAN 155158-75-1, 32.1 mg, 274 μmol) and DIEA (217 μL, 1.25 mmol). The brownish reaction mixture was stirred for 18 h at room temperature. The crude reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) and finally chiral chromatography (ChiralPak AD, heptane/ethanol 9:1) to deliver the desired compound (27.3 mg, 43%) as colorless oil. MS (ESI, m/z): 341.1 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15]([NH2:17])=O)=[CH:11]3)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH:1]1([CH2:4][N:5]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15](=[S:35])[NH2:17])=[CH:11]3)[CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c2[nH]1
Solvent: C1CCOC1
Product: NC(=S)c1cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A mixture of 7-[(cyclopropylmethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (264 mg), Lawesson's reagent (339 mg) and tetrahydrofuran (5 ml) was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of ethyl acetate-hexane (1:1) to give the title compound (243 mg, yield 88%) as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(F)ccc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)ccc1Cl

Procedure:
To a solution of 2-chloro-5-fluorobenzoic acid (22) (35.0 g, 200 mmol) in methanol (350 mL) was added cone. H2SO4 (5 mL). The mixture was heated at reflux for 24 h. Most of the solvent was evaporated, and the resulting mixture was diluted with water (300 mL). The mixture was extracted with EtOAc (150 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give methyl 2-chloro-5-fluorobenzoate (23).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:21][OH:22]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:21][OH:22])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCCC2=NO
Yield: 47 %

Procedure:
A solution of 6-methoxy-1-tetralone (40 g, 227 mmol), potassium carbonate (64 g, 462 mmol) and hydroxylamine.hydrochloride (63.2 g, 909 mmol) in methanol (500 mL) and water (56 mL) was refluxed for 2.5 hours. The potassium carbonate was filtered off, poured into ice (300 g) and water was added to total 1.5 L. The precipitate was collected to give 34.79 g (80%) of crude product, which recrystallized in methanol to give 20.4 g (47%) of a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:4].[Br:20]Br>C(O)(=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:20][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:19])([CH3:18])[CH3:1])=[C:7]([C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:17]=2)[CH:8]=1
Reactant: BrBr
Reactant: CC(C)(C)C(=O)Nc1ccccc1-c1ncccn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1ccc(Br)cc1-c1ncccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 113 %

Procedure:
To a room temperature suspension of 2,2-dimethyl-N-(2-pyrimidin-2-yl-phenyl)-propionamide (−117 grams, 437 mmoles) in acetic acid (1 L) was added bromine (67 mL, 1.31 moles) as a solution in 100 mL of acetic acid over a 1 hour period. The heterogenous mixture was stirred at room temperature for 5 hours over which time a thick precipitate formed. The mixture was then poured over ice, diluted with 1N Na2S2O3 (2 L), and stirred for 1 hour. The solids were filtered, resuspended in water (2 L), stirred for 1 hour, then filtered and washed with water again. The resulting solids were pumped to dryness at 50° C., resuspended in HOAc (1 L), and treated with bromine (22 mL, 430 mmoles) in acetic acid solution (20 mL) over a 20 minute period. The resulting heterogenous mixture was stirred for 5 hours, then quenched and treated as described above. The resulting solids were vacuum dried at 50° C. to afford the title compound (165 grams) as a tan powder.
Reaction SMILES: [K].[CH3:2][C:3]1[O:7][C:6]([CH:8]=[CH:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1.[Cl-].[Na+].[OH2:15]>>[CH2:9]([C:8]1[C:6](=[O:7])[CH2:5][CH:4]([OH:15])[C:3]=1[CH3:2])[CH:10]=[CH2:11]
Reactant: Cc1ccc(C=CCCO)o1
Reactant: O
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Product: C=CCC1=C(C)C(O)CC1=O
Reaction time: 0.58 h

Procedure:
Potassium secondary phosphate (1.12 g) and potassium primary phosphate (3.54 g) were dissolved in water (800 ml) to prepare a buffer solution (pH 6.2, 20° C.). In a reaction vessel, 5-methyl-2-furylallylcarbinol (20 g) and the entire amount of the buffer solution as prepared above were charged, and the temperature was elevated up to 150° C. in 35 minutes while stirring. The mixture was stirred at the same temperature for 4 hours, the inner pressure at this time being 3.8 kg/cm2. After cooling with ice, sodium chloride (100 g) was added thereto, and the mixture was extracted with methyl isobutyl ketone (200 ml) four times. The extract was concentrated at 60° C. under reduced pressure to remove methyl isobutyl ketone, whereby an oily substance (18.2 g) was obtained. The crude product was purified by distillation (130°-132° C./1.2 mmHg) to obtain 2-allyl-3-methyl-4-hydroxy-2-cyclopentenone (16.6 g). Yield, 83%.
Reaction SMILES: [N:1]1([C:6]([NH:8][C:9]2[NH:10][C:11]([CH3:16])=[CH:12][C:13](=[O:15])[N:14]=2)=[O:7])[CH:5]=[CH:4]N=C1.C[O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37]CN>C(OCC)(=O)C>[CH3:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:4][CH2:5][NH:1][C:6]([NH:8][C:9]1[NH:10][C:11]([CH3:16])=[CH:12][C:13](=[O:15])[N:14]=1)=[O:7]
Reactant: COCCOCCOCCOCCOCCOCCOCCN
Reactant: Cc1cc(=O)nc(NC(=O)n2ccnc2)[nH]1
Solvent: CCOC(C)=O
Product: COCCOCCOCCOCCOCCOCCOCCNC(=O)Nc1nc(=O)cc(C)[nH]1
Yield: 60.1 %

Procedure:
To a suspension of 4.38 g of 2-(1-imidazolylcarbonylamino)-6-methyl-4[1H]-pyrimidinone 1A (0.02 mol) in 200 ml of ethyl acetate were added 7.4 g of 2,5,8,11,14,17,20 heptaoxadocosan-22-amine (0.0218 mol). The reaction mixture was refluxed for 12 hours. The mixture was then allowed to return to room temperature, and was evaporated under reduced pressure. The residue was taken up in acetone (50 ml) and then filtered to remove the imidazole. The filtrate was evaporated under reduced pressure and then taken up again in 50 ml of acetone and filtered. The filtrate was evaporated under reduced pressure. 5.9 g of the expected product were thus obtained in the form of a pasty oil, in a yield of 60%. 1H and 13C NMR spectra compliant.
Reaction SMILES: Br[C:2]1[C:3]([CH2:10][O:11][CH2:12][O:13][CH3:14])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].[CH2:21]([NH2:23])[CH3:22]>O1CCCC1>[CH2:21]([NH:23][C:2]1[C:3]([CH2:10][O:11][CH2:12][O:13][CH3:14])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)[CH3:22]
Reactant: COCOCc1nc(OC)ccc1Br
Reactant: CCN
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNc1ccc(OC)nc1COCOC
Yield: 73.7 %

Procedure:
A solution of 3-bromo-6-methoxy-2-[(methoxymethoxy)methyl]pyridine (1.50 g, 5.72 mmol), tris(dibenzylideneacetone)(chloroform)dipalladium(0) (592 mg, 0.572 mmol), (2-biphenyl)di-t-butylphosphine (680 mg, 2.28 mmol), sodium t-butoxide (1.65 g, 17.2 mmol) and ethylamine (2.0 M solution in tetrahydrofuran, 15 mL, 30 mmol) in tetrahydrofuran (15 mL) was warmed to 135° C. over 3 minutes under microwave irradiation (500 W). The reaction mixture was cooled, then filtered through Celite, and washed with ethyl acetate. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain N-ethyl-6-methoxy-2-[(methoxymethoxy)methyl]pyridin-3-amine (954 mg, 74%) as yellow oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
15.26 g of 50% sodium hydride in oil is added, at 0° C., to a solution under inert gas of 50 g of parabromophenol in 320 ml of dimethylformamide, followed by agitation for 30 minutes at 0° C., then 37.7 ml of benzyl bromide is added. Agitation is carried out for 2 hours 30 minutes while allowing the temperature to return to 20° C., then the reaction mixture is poured into ice-cooled water, the precipitate is filtered and dried. 73.35 g of expected product is obtained. Rf: 0.85 (thin layer chromatography, support: silica, eluant: cyclohexane/ethyl acetate 7/3).
Reaction SMILES: [O:1]=[C:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO[CH:11]([N:14]([CH3:16])[CH3:15])OC>>[CH3:11][N:14](/[CH:16]=[C:3](/[C:2](=[O:1])[CH3:8])\[C:4]([O:6][CH3:7])=[O:5])[CH3:15]
Reactant: COC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Product: COC(=O)/C(=C\N(C)C)C(C)=O
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Into a 250-mL round-bottom flask, was placed methyl 3-oxobutanoate (10.8 g, 92.6 mmol) and (dimethoxymethyl)dimethylamine (12.7 mL, 95.3 mmol). The resulting solution was stirred for 2.5 h at 80° C., then concentrated under reduced pressure to yield 14.5 g (crude) of the title compound as a red solid.