Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CO2
Reactant: CS(=O)(=O)Cl
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(C)(=O)=O)cc3CO1)CO2
Yield: 42.6 %

Procedure:
Prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 6) (150 mg, 0.482 mmol) and methanesulfonyl chloride (61 mg, 0.53 mmol) according to the procedure described for Example 27. Obtained the title compound as a white solid (80 mg, 43%), MS (ISP) m/e=390.1 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][C:6]3=[O:11])=[N:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=C1CCc2c(O)cccc21
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.6 %

Procedure:
1.0 g of 4-hydroxy-1-indanone, 1.07 g of 2-chloro-5-nitropyridine and 5 g of anhydrous potassium carbonate were dissolved in 10 ml of N,N-dimethylformamide (DMF) and the mixture was stirred at room temperature for 17 hours. After the completion of the reaction, 50 ml of water was added to the reaction solution and the solution was extracted with ethyl acetate. After the organic (ethyl acetate) layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off. The resulting residue was recrystallized from ethyl acetate to obtain the titled compound (1.36 g, pale yellow powder).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7](S(C2C=CC=CC=2)(=O)=O)[C:8]2[C:13]([C:14]=1[S:15]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:17])=[O:16])=[CH:12][C:11]([Br:30])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.O>[Br:30][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[C:14]2[S:15]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:16])=[O:17]
Reactant: CCOC(=O)c1c(S(=O)(=O)NCCCCC(=O)OC(C)(C)C)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCNS(=O)(=O)c1c(C(=O)O)[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl-5-bromo-3-{[(5-tert-butoxy-5-oxopentyl)amino]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate (63 mg, 0.98 mmol) in 2 mL of 3:1 THF/water was added NaOH (2 pellets). After stirring at room temperature for 6 hours, another portion of NaOH was added. After 16 hours, the reaction was partitioned between 3N HCl and dichloromethane. The aqueous phase was extracted three times with dichloromethane, and the combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo to give the titled product as a white foam. ESI+ MS: 419 [M-CH2═CMe2]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:34])=[C:24]([N:26]([CH2:31][C:32]#[CH:33])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:34][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH2:31][C:32]#[CH:33])[S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: C#CCN(c1cc(C(=O)C=CN(C)C)ccc1F)S(C)(=O)=O
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#CCN(c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1F)S(C)(=O)=O
Yield: 61.3 %

Procedure:
A mixture of 0.108 g (0.56 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.198 g (0.61 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-prop-2-ynyl-methanesulfonamide in 10 ml of glacial acetic acid was refluxed for 2 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 156 mg of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-prop-2-ynyl-methanesulfonamide as a solid (yield 61%).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][N:13]([CH3:26])[C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([N+:23]([O-])=O)=[CH:22][C:16]=2[N:15]=1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>CCO>[CH3:1][N:2]([CH2:11][CH2:12][N:13]([CH3:26])[C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:16]=2[N:15]=1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CCN(C)c1nc2cc([N+](=O)[O-])ccc2[nH]1)C(=O)c1ccccc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(CCN(C)c1nc2cc(N)ccc2[nH]1)C(=O)c1ccccc1
Reaction time: 8 h
Yield: 94.1 %

Procedure:
A mixture of N-methyl-N-[2-[methyl(5-nitro-1H-benzimidazol-2-yl)amino]ethyl]benzamide (1.30 g, 3.68 mmol) and SnCl2.2H2O (4.15 g, 18.39 mmol) in EtOH (15 mL) was heated under reflux for 1 hour. The mixture was cooled and made basic (pH8) with 2.5N NaOH. The precipitate was removed by filtration and the filtrate was concentrated. The residue was stirred with EtOAc (150 mL) overnight, dried (MgSO4), and concentrated to give 1.12 g (94%) of a green foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][CH:10]=[C:9]([CH2:12][OH:13])[CH:8]=1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=1
Reactant: OCc1c[nH]c(-c2ccccn2)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1c[nH]c(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
To a solution (50 mL) of [5-(pyridin-2-yl) -1H-pyrrol-3-yl]methanol (0.96 g) in acetonitrile were added tetra-n-propylammonium perruthenate (194 mg), N-methylmorpholine N-oxide (2.98 g) and molecular sieves 4A powder (5 g), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as colorless crystals (yield 270 mg, 29%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.[OH-].[K+].Cl>CO.C(O)CCCCCCC>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCCCO
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 22.4 %

Procedure:
To a mixture of 307 mg (purity: 98.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 833 mg (5.57 mmol) of 2-cyclopropyl-6-methylphenol were added 1-octanol (3.36 mL) and 324 mg (5.50 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 113 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 23%) and 1.4 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.3%) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:26](=[O:27])[C:11]3=[CH:12][NH:13][C:14]([CH3:25])=[C:15]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:26](=[O:27])[C:11]3=[CH:12][NH:13][C:14]([CH3:25])=[C:15]([C:16]4[CH:24]=[CH:23][CH:22]=[C:18]([C:19]([N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:20])[CH:17]=4)[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(C(=O)O)c1
Reactant: C1CCNC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(C(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To a solution of 3-[2-(4-chlorophenyl)-3,5-dihydro-6-methyl-3-oxo-2H-pyrazolo[4,3-c]pyridin-7-yl]benzoic acid (65 mg, 0.171 mmol) in anhydrous N,N-dimethylacetamide (2 ml) was added pyrrolidine (15.7 ml, 0.188 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (48.0 mg, 0.188 mmol), then, dropwise, anhydrous triethylamine (52.5 ml, 0.376 mmol). The mixture was stirred under nitrogen at room temperature for 18 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 3-5% MeOH/CH2Cl2) to give 63.2 mg (85%) of the title compound as a yellow solid; mp 253-255° C.; 1H NMR (360 MHz, DMSO-d6) δ1.85 (4H, m), 2.29 (3H, s), 3.49 (4H, br q, J 6.9 Hz), 7.41 (2H, d, J 9.0 Hz), 7.55-7.59 (3H, m), 7.66 (1H, s), 8.12 (2H, d, J 9.0 Hz), 8.58 (1H, s), 12.49 (1H, br s); MS (ES+) m/z 433/435 [H]+. Anal. found: C, 63.85; H, 4.96; N, 12.33. C24H21ClN4O2.H2O requires: C, 63.93; H, 5.14; N, 12.42%.
Reaction SMILES: O[N:2]=[C:3]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[CH2:5][CH2:4]1.[OH-].[Na+]>CCO.O.[Ni]>[CH2:5]1[C:6]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH:3]([NH2:2])[CH2:4]1
Reactant: ON=C1CCc2c1[nH]c1ccccc21
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC1CCc2c1[nH]c1ccccc21
Yield: 90.1 %

Procedure:
To a stirred solution of 3-hydroxyimino-1,2,3,4-tetrahydrocyclopent[b]indole (6 g) in 150 ml of 95% EtOH at 0° C. was added a nickel alloy (Harshaw, Ni-1000P, 10 g) followed by 12.9 grams of sodium hydroxide in 150 ml water. The ice bath was removed after 0.5 hour and the mixture was stirred an additional hour and filtered. The EtOH was removed in vacuo and the product crystallized to provide 5.0 grams of solid. A sample was recrystallized from toluene to provide analytically pure material.
Reaction SMILES: [K].Cl.O.[NH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][NH:18]2)=[CH:14][CH:13]=1>CO>[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:7]3[CH2:6][CH2:5][NH:4][CH2:9][CH:8]=3)=[CH:17][NH:18]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(C3=CCNCC3)c[nH]c2c1
Yield: 92.7 %

Procedure:
To a solution of potassium hydroxyde (16 g) in methanol were added at 5° C. 4-piperidone hydrate hydrochloride (30 g) and a solution of 6-methyl-1H-indole (10 g) in methanol (50 ml). The mixture was refluxed for 16 hours. After cooling precipitated inorganic salts were filtered off. Methanol was evaporated and the remaining oil was dissolved in ethyl acetate (200 ml) and subsequently washed with brine (2×100 ml). After drying (anh. MgSO4) the solvent was evaporated leaving 15 g of crude 6-methyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole, which was used without further purification. The pure tetrahydropyridyl derivative crystallized from diethyl ether. Mp: 150°-152° C. To a solution of 1-(2-chloroethyl)-3-(2-propyl)-2-imidazolidinon (32 g) in MIBK (500 ml) were added 6-methyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (15 g), potassium carbonate (16 g) and potassium iodide (5 g). The mixture was refluxed for 19 hours and finally filtered while still hot. MIBK was evaporated and the resulting oil was dissolved in ethyl acetate (500 ml) and washed with brine (2×100 ml). After drying (anh. Na2SO4) ethyl acetate was evaporated. The remaining oil was stirred with diethyl ether (200 ml) and the precipitated, crystalline 3-[1-[2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl]-1,2,3,6-tetrahydro-4-pyridyl]-6-methyl-1H-indole was filtered off. Yield: 14.5 g. Mp: 170°-174° C. To a solution of the thus prepared imidazolidinon derivative (14 g) in acetic acid (300 ml) was added PtO2 (600 mg). This mixture was hydrogenated in a Parr apparatus at 3 ato. for 72 hours. The catalyst was filtered off and most of the acetic acid was evaporated in vacuo. The remaining oil was dissolved in H2O and pH was adjusted to 9-10 by addition of dil. NaOH solution. The title compound 14a was extracted with dichloromethane (2×200 ml) and isolated as above. The crude product was purified by eluting (eluent: ethyl acetate/dichloromethane/ethanol/triethyla-mine 40:40:20:5) through silica gel. Yield: 4.5 g. Mp: 185° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[C:3]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1.CCCCCC.C([Li])CCC.[I:28]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C>[CH:14]1([CH2:13][O:12][C:3]2[C:4]([O:8][CH2:9][O:10][CH3:11])=[CH:5][CH:6]=[CH:7][C:2]=2[I:28])[CH2:16][CH2:15]1
Reactant: COCOc1cccc(Br)c1OCC1CC1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Product: COCOc1cccc(I)c1OCC1CC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 106.2 %

Procedure:
To 76 ml of diethyl ether solution containing 24.1 g (84 mmol) of 1-bromo-2-cyclopropylmethoxy-3-methoxymethoxybenzene obtained in Reference example 12-(a) was added dropwise 53.4 ml (84 mmol) of 1.58M n-butyl lithium hexane solution at −60° C. or lower under argon atmosphere. The mixture was stirred at the same temperature for further 30 minutes, raised to −30° C., and then, 50 ml of diethyl ether solution containing 21.3 g (84 mmol) of iodine was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred at the same temperature for 30 minutes, and then, gradually raised to room temperature. After completion of the reaction, to the reaction mixture was added 95 ml of 2% aqueous sodium thiosulfate solution, and the mixture was stirred for 1 hour. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 29.8 g of the title compound as a reddish oil substantially quantitatively.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13]>>[C:1]1([CH2:7][C:8]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C[C@H](N)C(=O)O
Product: C[C@H](NC(=O)Cc1ccccc1)C(=O)O

Procedure:
Using General Procedure II-C, the title compound was prepared from phenylacetyl chloride (Aldrich) and L-alanine (Aldrich) as a solid having a melting point of 102-104° C.
Reaction SMILES: [CH2:1]=[O:2].S(=O)(=O)(O)O.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.C(C1C=CC=CC=1)C>>[C:16]1([CH:1]=[O:2])[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc2ccccc2c1
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: CCc1ccccc1
Product: O=Cc1cccc2ccccc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 105.6 %

Procedure:
A bottom-removable four-necked flask having an inner volume of 2 L and equipped with a Dimroth condenser, a thermometer and a stirring blade was charged with 912 g of an aqueous 37% by mass formalin solution (11.2 mol as formaldehyde, produced by Mitsubishi Gas Chemical Company, Inc.) and 485 g of 98% by mass sulfuric acid (produced by Mitsubishi Gas Chemical Company, Inc.) in a nitrogen stream, 288 g of naphthalene (2.25 mol, produced by Wako Pure Chemical Industries, Ltd.) was dropped thereto over 6 hours while stirring under reflux under ordinary pressure at about 100° C., and the reaction was performed as it was for further 1 hour. Thereto was added 500 g of ethylbenzene (produced by Wako Pure Chemical Industries, Ltd.) as a dilution solvent and left to still stand, and then an aqueous phase as a lower phase was removed. Furthermore, the resultant was subjected to neutralization and washing with water, and ethylbenzene and unreacted naphthalene were distilled off under reduced pressure to thereby provide 371 g of a naphthalene formaldehyde resin as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:27])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:26])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:28]([OH:31])[C:29]#[CH:30]>C1COCC1.CCOC(C)=O.[Cu]I>[Cl:26][C:22]1[N:23]=[CH:24][NH:25][C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([C:30]#[C:29][CH2:28][OH:31])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:27])=[O:20]
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F)c1[nH]cnc1Cl
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#CCO)c2)c1F)c1[nH]cnc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (100 mg, 0.203 mmol), dichlorobisthiphenylphosphinepalladium(II) (14.22 mg, 0.020 mmol), copper(I) iodide (1.929 mg, 10.13 μmol) and TEA (0.141 ml, 1.013 mmol) in THF (5 ml) was added propargyl alcohol (22.72 mg, 0.405 mmol) and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-chloro-5-(3-hydroxy-1-propyn-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (18 mg, 0.038 mmol, 19% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1([CH3:34])[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:14]([CH2:23][CH2:24][C:25]([N:27]2[C@H:31]([CH3:32])[CH2:30][O:29][C:28]2=[O:33])=[O:26])[CH2:13][O:12]1.[C:35]([O:39][C:40](=[O:43])[CH:41]=[CH2:42])([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:35]([O:39][C:40](=[O:43])[CH2:41][CH2:42][C@@H:24]([C:25]([N:27]1[C@H:31]([CH3:32])[CH2:30][O:29][C:28]1=[O:33])=[O:26])[CH2:23][C@H:14]1[CH2:13][O:12][C:11]([CH3:10])([CH3:34])[N:15]1[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])([CH3:38])([CH3:37])[CH3:36]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C[C@@H]1COC(=O)N1C(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COC(=O)N1C(=O)[C@H](CCC(=O)OC(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
At 0° C., 1.0M TiCl4 in CH2Cl2 solution (8.55 mL, 0.7 eq) was added to CH2Cl2 (100 mL) followed by the addition of 1.0M TiCl(Oi-Pr)3 in hexanes solution (4.28 mL, 0.35 eq) and stirred 5 min DIPEA (2.87 mL, 1.35 eq) was added and stirred 15 min. A solution of (S)-tert-butyl 2,2-dimethyl-4-(3-((R)-4-methyl-2-oxooxazolidin-3-yl)-3-oxopropyl)oxazolidine-3-carboxylate (5.28 g, 12.22 mmol) in CH2Cl2 (50 mL) was added. The reaction mixture was stirred 1 hr at 0° C. To the solution, t-butylacrylate (2.22 mL, 1.25 eq) was added and the mixture was left stirred over 48 hr with concomitant warming to rt. The mixture was concentrated, partitioned between EtOAc (300 mL) and 1% HCl solution (100 mL). The organic layer was washed with sat. NaHCO3 solution (60 mL), brine (60 mL), dried over Na2SO4. After filtration and concentration, the residue was purified by ISCO (120 g column, 0˜35% EtOAc in Hexanes gradient) to afford 4.12 g (60%) (S)-tert-butyl 4-((R)-5-tert-butoxy-2-((R)-4-methyl-2-oxooxazolidine-3-carbonyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate as a yellowish solid. MS ESI+ve m/z 583 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[CH2:20](O)[C:21]#C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:6][CH:5]=1)[C:20]#[CH:21]
Reactant: C#CCO
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C#CCOC(=O)c1ccc(OC(C)CCCC(C)C)cc1

Procedure:
13 g of p-[(1,5-dimethylhexyl)oxy]benzoic acid methyl ester is heated to reflux with 9 g of propargyl alcohol and 0.1 g of p-toluenesulphonic acid. The excess propargyl alcohol is thereupon slowly (5 hrs.) distilled off. The residue is poured onto water and extracted with diethyl ether. The ether phase is dried with sodium sulfate and evaporated. There is obtained dark-yellow p-[(1,5-dimethylhexyl)oxy]benzoic acid propargyl ester which is purified on Kieselgel.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:7][CH:6]=1)[CH2:2][CH2:3]C.[CH2:18](I)CCC>CCOC(C)=O>[CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:15])([CH3:16])[CH3:17])(=[O:11])=[O:12])=[CH:7][CH:6]=1)[CH:2]([CH3:3])[CH3:18]
Reactant: CCCCc1ccc(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCI
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(S(=O)(=O)NC(C)(C)C)s1

Procedure:
The titled compound was prepared using the procedure described for the synthesis of 5-butyl-2-(N-t-butylaminosulfonyl)-thiophene by substituting isobutyliodide for butyliodide. Rf=0.37 (6:1 Hex/EtOAc).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][N:14]=1>CO>[N:16]1[CH:17]=[CH:18][C:13]([CH:12]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[N:14][CH:15]=1
Reactant: Cc1ccncn1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CO
Product: O=C1c2ccccc2C(=O)C1c1ccncn1

Procedure:
7.87 g (53.1 mmol) phthalic acid anhydride and 22 ml (0.24 mol) 4-methylpyrimidine are stirred for 1 h at 140° C. and for 4 h at 21° C. The reaction mixture is then stirred with 15 ml methanol, filtered, and the residue washed with methanol. Further product is obtainable by evaporating the filtrate and stirring the residue with water: m.p.: 168-169° C.); Anal. calc.(C13H8N2O2) C, 69.64%; H, 3.60%; N, 12.49%. found C, 69.8%; H, 3.7%; N, 12.4%; FAB MS (M+H)+=225.
Reaction SMILES: [C:1]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:19][NH2:20].O>CCO>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[C:9]3[S:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:16])[NH:19][N:20]=2)=[CH:3][CH:4]=1
Reactant: NN
Reactant: CCOC(=O)c1ccsc1C(=O)c1ccncc1
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccncc2)c2sccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
The mixture of ethyl 2-isonicotinoylthiophene-3-carboxylate (200 mg, 0.77 mmol) from example 2.2 in NH2NH2.H2O (2 mL) and EtOH (10 mL) was stirred at room temperature for 30 min. The mixture was filtered and the solid dried to obtain the title compound (150 mg, 85.1% yield).