Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43])(OCC)=O>O.C(#N)C>[C:34]1(=[O:43])[N:2]([CH:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]12
Reactant: CCCCOc1cc(C(N)CC(=O)OC)ccc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCCOc1cc(C(CC(=O)OC)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
To a stirred solution of methyl 3-amino-3-(3-butoxy-4-methoxyphenyl)propionate hydrochloride (0.95 g, 3.0 mmol) and sodium carbonate (0.32 g, 3.0 mmol) in a mixture of water (10 mL) and acetonitrile (10 mL) was added N-carbethoxyphthalimide (0.68 g, 3.0 mmol). The resulting solution was stirred for 3 hours at room temperature. The acetonitrile was removed in vacuo. To the resulting mixture was added ether (5 mL) and the mixture was stirred at room temperature overnight allowing the ether to evaporate. The resulting white solid was filtered. The solid was washed with water, air dried, and dried in vacuo (60° C., <1 mm) to afford 1.1 g (89%) of methyl 3-phthalimido-3-(3-butoxy-4-methoxyphenyl)propionate as a white solid: mp 54°-55° C.; 1H NMR (CDCl3) δ5 7.86-7.63 (m, 4H), 7.16-7.05 (m, 2H), 6.85-6.76 (m, 1H), 5.76 (dd, J=5.9, 10 Hz, 1H), 4.02 (t, J=6.7 Hz, 3.86-3.71 (m, 1H), 3.83 (s, 3H), 3.63 (s, 3H), 3.24 (dd, J=5.9, 16.5 Hz, 1H), 1.89-1.73 (m, 2H), 1.59-1.41 (m, 2H), 1.04-0.89 (m, 3H); 13C NMR (CDCl3) δ5 171.1, 168.1, 149.2, 148.5, 133.9, 131.8, 130.9, 123.3, 120.2, 112.7, 111.4, 68.6, 55.9, 51.9, 50.7, 35.9, 31.1, 19.2, 13.9; HPLC (Waters Nova-Pak C18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 55/45, acetonitrile/0.1% aqueous phosphoric acid) 6.5 min, 100%, Anal. Calcd. for C23H2 NO6. Theoretical: C, 67.14; H, 6.12; N, 3.40. Found: C, 66.89; H, 6.15; N, 3.31.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[N:13]=1)[CH2:9][C:10]#[CH:11]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[N:13]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[O:16][N:15]=1
Reactant: Ic1ccccn1
Reactant: C#CCCc1nc(-c2ccccc2OC)no1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1noc(CCC#Cc2ccccn2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.6 %

Procedure:
In a dry reaction tube containing in suspension copper iodide (12 mg, 0.07 mmol) and triethylamine (4.1 mL, 29 mmol), were added 2-iodopyridine (139 μL, 1.3 mmol) and Pd(PPh3)2Cl2 (46 mg, 0.07 mmol) under N2. A yellow suspension is obtained and after a few minutes of string at room temperature, was added a solution 5-(but-3-ynyl)-3-(2-methoxyphenyl)-1,2,4-oxadiazole (299 mg, 1.3 mmol) in triethylamine (0.7 mL) under N2. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 20 h under N2. Triethylamine was removed under reduce pressure and the crude product was purified by flash chromatography (Prepacked column 10 g, cyclohexane/AcOEt: from 60/40 to 50/50 as eluent) to afford 50 mg of 2-(4-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (13%) as brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:7].CI.[H-].[Na+].[C:25](OCC)(=O)C>C1COCC1.O>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH2:16][CH:17]([CH3:18])[CH3:19])[N:5]([CH3:25])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:7]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccn1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)N(C)C(=O)OCc1ccccn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 46 %

Procedure:
N-(2-pyridinylmethoxycarbonyl)-L-leucine methyl ester (490 mg, 1.75 mmol) was dissolved in THF (7.0 mL) and methyl iodide (0.435 ml, 6.99 mmol) was added. The reaction mixture was cooled to 0° C. in a flask protected from moisture. Sodium hydride dispersion (236 mg, 2.62 mmol) was added cautiously and the suspension was sired for 5 hours at room temperature. Ethyl acetate was then added, followed by water, dropwise. The solution was concentrated in vacuo, and the oily residue partitioned between ether and water. The organic layer was washed with sated aqueous NaHCO3 and the combined aqueous extracts acidified to pH 3 with citric acid. The product was extracted with ethyl acetate, the extract was washed with water, 5% aqueous sodium thiosulfate and water, dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography on silica gel (ethyl acetate/hexane, 3:1) to give a yellow oil (235 mg, 46%). MS (ESI): 295.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(CNS(C)(=O)=O)c1ccc(-c2cccc(F)c2)cc1
Temperature: 100 °C
Yield: 9.6 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.1 g (7.7 mmol) of 3-fluorobenzeneboronic acid and 1.1 g (7.7 mmol) of potassium carbonate in 30 mL of toluene was added 0.2 g (0.3 mmol) of bis(triphenylphosphine)palladium(II) dichloride. The mixture was heated to 100° C. for 16 hours, cooled to ambient temperature and diluted with 20 mL of ethyl acetate. The mixture was washed once with 25 mL water and the organic portion was separated. The aqueous portion was extracted three times with ethyl acetate and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 75 g silica gel (20% ethyl acetate/toluene) followed by recrystallization from ethyl ether, filtration and drying in vacuo at 60° C. afforded 0.15 g (9%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:19][C:18]=3[F:31])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].O1CCC[CH2:35]1.S(C1C=CC(C)=CC=1)(OC)(=O)=O>O.CN(C)C=O>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][O:29][CH3:35])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:19][C:18]=3[F:31])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@@H]4CO)cc3F)CC2)c(C)c1
Reactant: C1CCOC1
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H]1CCC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Using (R)-5-hydroxymethylpyrrolidin-2-one (138 mg) and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (392 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 1, (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-hydroxymethylpyrrolidin-2-one (330 mg) was obtained. To a mixture of the obtained (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-hydroxymethylpyrrolidin-2-one (330 mg) and sodium hydride (37 mg) were added tetrahydrofuran and N,N-dimethylformamide, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added methyl tosylate (117 μL), and the mixture was further stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-methoxymethylpyrrolidin-2-one. The obtained (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-methoxymethylpyrrolidin-2-one was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate was added and the mixture was stirred. The reaction mixture was concentrated under reduced pressure, diethyl ether was added, and the precipitate was collected by filtration to give the title compound (48 mg).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[N:25][C:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:23]2)[C:6]1=[O:34])[CH2:2][CH2:3][CH3:4].N1CCOCC1.CO>C1COCC1.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>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[N:25][C:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:23]2)[C:6]1=[O:34])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCn1cnc(Cc3ccccc3)n1)c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCN1
Product: CCCCn1c(=O)n(CCCn2cnc(Cc3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 18 h
Yield: 61.9 %

Procedure:
A solution of 3-butyl-8-chloro-1-{3-[3-(phenylmethyl)-1H-1,2,4-triazol-1-yl]propyl}-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (669 mg, 1.39 mmol) in THF (7 ml) was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh3)4 (160 mg, 0.14 mmol) was added and the mixture degassed once more. Morpholine (1.2 ml, 13.9 mmol) was added and the mixture was stirred under nitrogen for 18 h, then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated, giving a yellow residue. MeOH was added and then passed down an aminopropyl SPE with the product eluting with 2-3% AcOH/MeOH. The product fractions were combined and concentrated giving a pale yellow solid (380 mg). Approximately a quarter of the material was purified by autoprep HPLC and rest was crystallised from MeOH:DMSO (1:1) giving the title compound as a white solid (125 mg, 31%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[S:11][CH:12]([CH3:14])[CH3:13].CO.[H][H]>[Ni].O>[CH:12]([S:11][C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:8])([CH3:14])[CH3:13]
Reactant: CC(C)Sc1c(Cl)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: O
Product: CC(C)Sc1ccccc1N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
34.7 g of 2-chloro-6-nitrophenyl-isopropylsulfane, 140.0 g of methanol and 1 g of Raney nickel 55, as the catalyst (water-moist), were initially introduced into a 0.3 l steel autoclave. After the air had been displaced with nitrogen and hydrogen, hydrogen was forced in at room temperature up to a pressure of 80 bar, while stirring the mixture, a slight increase in temperature already being observed. The mixture was heated to 60° C., while continuing to stir and keep the hydrogen pressure constant. After about 2 hours, the uptake of hydrogen had ended. The mixture was then cooled to room temperature, the hydrogen was let down, the catalyst was filtered off with suction and washed with methanol and the combined filtrates were concentrated. Crude yield: 29.6 g of 2-amino-6-chlorophenyl-isopropylsulfane with a purity of 99.5% (GC), corresponding to 97.5% of theory. The content of 2-isopropylmercaptoaniline formed by hydrogenating dehalogenation was only 0.1%. Furthermore, only 0.1% of impurities due to 3-chloroaniline, formed by hydrogenating desulfurization, were found.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=O)[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([NH:24][S@@:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12]
Reactant: COc1cc(C(C)=O)cnc1OCC(F)(F)F
Reactant: CC(C)(C)[S@](N)=O
Product: COc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)(F)F
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (0.29 g, white solid) from 1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.25 g, 0.99 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[O:7]=[CH:8][C:9]([Cl:12])([Cl:11])[Cl:10].O>C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:8]([OH:7])[C:9]([Cl:12])([Cl:11])[Cl:10]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Cn1cccc1
Solvent: O
Solvent: c1ccccc1
Product: Cn1cccc1C(O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of N-methylpyrrole (810 mg, 10 mmol) dissolved in benzene (10ml) was added dropwise a solution of chloral (1.47 g, 10 mmol) dissolved in benzene (5 ml) under ice-cooling for 40 minutes. After the mixture was stirred for 1 hour at room temperature, water was added thereto and the mixture was extracted with ether. The extract was dried over sodium sulfate and concentrated to afford 1-methyl-2-(2',2',2'-trichloro-1'-hydroxyethyl)pyrrole (2.04 g) as an oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:26]=[CH:25][C:13]2[N:14]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:15]([CH2:17]O)=[N:16][C:12]=2[CH:11]=1.S(Cl)(Cl)=O.[I-].[Na+].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:26]=[CH:25][C:13]2[N:14]([CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:15]([CH2:17][NH:40][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:16][C:12]=2[CH:11]=1
Reactant: NCc1ccccc1
Reactant: OCc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Agent: [I-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CNCc2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To 5-(benzoxazol-2-yl)-2-hydroxymethyl-1-(tetrahydropyran-4-yl)benzimidazole (see Working Example 13-2) (168 mg, 0.481 mmol) was added thionyl chloride (1.5 mL), and this was heated to reflux with stirring for 2 hours. After the reaction was complete, this was cooled to room temperature and concentrated. The crystals obtained were suspended in tetrahydrofuran, and to this was added sodium iodide (108 mg, 0.722 mmol) and benzylamine (258 mg, 2.41 mmol), and this was heated to reflux with stirring for 1.5 hours. After the reaction was complete, this was cooled to room temperature, water was added, and this was extracted with ethyl acetate. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give an residue that was purified by silica gel column chromatography to yield the title compound (182 mg, 86% yield) as a colorless amorphous mass.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH3:9])=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: CC(Oc1ccncc1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccncc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
A mixture of 4-(1-(pyridin-4-yloxy)ethyl)benzoic acid (127 mg, 0.5 mmol), N-hydroxybenzotriazole (101.25 mg, 0.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg, 0.75 mmol) and triethylamine (151 mg, 1.5 mmol) in dichloromethane (50 mL) was stirred for 30 minutes at room temperature. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. The mixture was washed with water (10 mL×3). The organic layer was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(pyridin-4-yloxy)ethyl)benzamide (57 mg, 30%). LRMS (M+H+) m/z: calcd 377.17. found 377. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, CD3OD): δ 8.23 (d, J=5.1 Hz, 2H), 7.78 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 6.93-6.91 (m, 2H), 6.08 (s, 1H), 5.62 (q, J=6.3 Hz, 1H), 4.47 (s, 2H), 2.34 (s, 3H), 2.23 (s, 3H), 1.64 (d, J=6.3 Hz, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.C(#N)C.[F:27][C:28]([F:33])([F:32])[C@@H:29]1[CH2:31][O:30]1>O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][N:11]([CH2:31][C@H:29]([OH:30])[C:28]([F:33])([F:32])[F:27])[CH2:12][CH2:13][O:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1cccc(C2CNCCO2)c1
Reactant: FC(F)(F)[C@@H]1CO1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H](CN1CCOC(c2cccc(Cl)c2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.4 %

Procedure:
In a 50 mL round-bottomed flask, 2-(3-chlorophenyl)morpholine hydrochloride (OChem., Lot #100301A1, 200 mg, 854 μmol) and DIEA (265 mg, 358 μl, 2.05 mmol) were combined with acetonitrile (2.5 ml) to give an off-white suspension. (S)-2-(trifluoromethyl)oxirane (287 mg, 2.56 mmol) was added. The reaction mixture was stirred at room temperature for 48 h. The reaction was complete by LCMS (MH+=310). The reaction mixture was poured into 50 mL H2O and extracted with diethyl ether/dichloromethane 10:1 (3×50 mL). The organic layers were combined, washed with saturated NaCl (1×50 mL), dried over MgSO4 and concentrated in vacuo to afford 218 mg (82% yield) of (2S)-3-(2-(3-chlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol as an amber oil. (MH+=310).
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Cl.[OH:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=4[OH:23])[CH2:29]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: COc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc(-c2nc(C(=O)N3CCc4c(ccc(OC)c4O)C3)c3ccccc3n2)cc1
Yield: 16 %

Procedure:
Reaction of 2-(4-methoxylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 22 (16% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.65 and 2.89 (2t, 2H), 3.47 and 4.03 (2t, 2H), 3.74-3.87 (3s, 6H), 4.38 and 4.91 (2s, 2H), 6.32 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.09-7.15 (m, 2H), 7.63-7.73 (m, 1H), 7.81-7.93 (2d, 1H), 8.02-8.12 (m, 2H), 8.44-8.51 (m, 2H), 8.68 and 8.73 (2s, 1H); MS (ESI) m/z 442 ([M+H]+).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]#[N:8])[C:4]([C:9]#[N:10])=[CH:3][CH:2]=1.[CH3:11][O-:12].[Na+].[CH3:14][OH:15]>>[CH3:11][O:12][C:7]1([O:15][CH3:14])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:9](=[NH:10])[NH:8]1
Reactant: CO
Reactant: N#Cc1ccccc1C#N
Reactant: C[O-]
Agent: [Na+]
Product: COC1(OC)NC(=N)c2ccccc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
25.6 parts of o-phthalodinitrile (0.2 mol) are stirred into 200 parts of methanol. 4.5 parts of sodium methylate solution, 30% strength in methanol (0.025 mol), are added at 20° C. and the mixture is stirred at 20° C. for 16 hours. A solution of 1,1-dimethoxy-3-imino-isoindoline is obtained.
Reaction SMILES: O1C=CC=C1C=C[C:8]([N:10]=[N+]=[N-])=[O:9].[CH3:13][CH2:14][O:15][CH2:16][CH3:17].[C:18]1(C)C=CC=C[CH:19]=1>>[O:15]1[C:16]2[CH:19]=[CH:18][NH:10][C:8](=[O:9])[C:17]=2[CH:13]=[CH:14]1
Reactant: [N-]=[N+]=NC(=O)C=Cc1ccco1
Reactant: CCOCC
Reactant: Cc1ccccc1
Product: O=c1[nH]ccc2occc12
Temperature: 170 °C
Reaction time: 0.5 h

Procedure:
3-(Furan-2-yl)-acryloyl azide (12.6 g) was dissolved in 100 ml of toluene and the resultant solution was heated up to 120° C. and stirred for 30 min. After evaporation of solvent, o-dichlorobenzene (100 ml) and a few flakes of iodine were added and resultant reaction mixture was heated up to 170° C. and stirred for 2 hours. The mixture was cooled down to ambient temperature and to this was added Et2O (100 ml). The undissolved matter was filtered off and the filtrate was poured into a mixture of Et2O (100 ml), 1N NaOH (100 ml) and water (100 ml). The corresponding aqueous layer was collected, which was acidified by 2N HCl and extracted with ethyl acetate. The organic layer was separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue was precipitated from Et2O, which was collected and dried under the reduced pressure to give 5H-furo[3,2-c]pyridin-4-one (6.7 g) 1H NMR (400 MHz, DMSO-d6) ppm 11.44 (brs, 1H), 7.87 (d, J=2.3 Hz, 1H), 7.29 (d, J=7.1 Hz, 1H), 6.93 (dd, J=2.1, 0.9 Hz, 1H), 6.66 (dd, J=0.8, 7.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.ClC1C(Cl)=NC2C(=CC=CC=2)N=1.S([O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH3:39])=[CH:34][CH:33]=1)(O)(=O)=O>>[CH3:39][N:38]([C:35]1[CH:36]=[CH:37][C:32]([OH:31])=[CH:33][CH:34]=1)[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: Clc1cc2nc(Cl)c(Cl)nc2cc1Cl
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Agent: Clc1nc2ccccc2nc1Cl
Product: CN(c1ccc(O)cc1)c1nc2cc(Cl)c(Cl)cc2nc1Cl

Procedure:
2,3,6,7-Tetrachloroquinoxaline (mp 176° C.; prepared following essentially the same procedure as that referred to in Example 3 Part (a) for the preparation of 2,3-dichloroquinoxaline) was reacted with 4-(N-methylamino)phenol sulfate, following essentially the same procedure as that described in Example 1 Part (a), to give 4-[N-methyl-N-(3,6,7-trichloro-2-quinoxalinyl)amino]phenol.