Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7](=[O:25])[CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([C:15]3[CH:16]=[N:17][C:18]4[NH:19][CH2:20][CH2:21][CH2:22][C:23]=4[CH:24]=3)[CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl.CCOC(C)=O>[C:32]([N:19]1[C:18]2[N:17]=[CH:16][C:15]([C:13]3[CH:14]=[C:9]([CH2:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:25])[CH:10]=[N:11][CH:12]=3)=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)(=[O:34])[CH3:33]
Reactant: O=C(Cc1cncc(-c2cnc3c(c2)CCCN3)c1)N1CCOCC1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCCc2cc(-c3cncc(CC(=O)N4CCOCC4)c3)cnc21
Reaction time: 16 h

Procedure:
1-Morpholin-4-yl-2-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-ethanone (62.4 mg, 0.184 mmol) is dissolved in DCM (2 mL). Pyridine (0.089 mL, 1.11 mmol) is added. Acetyl chloride (1.0M in DCM, 0.55 mL, 0.55 mmol) is added dropwise and the mixture is stirred for 16 h. The mixture is diluted with EtOAc (50 mL), washed with water (3×5 mL), and brine, dried over sodium sulfate, filtered, and concentrated. The resulting crude product is purified by normal phase chromatography using 0-6% MeOH in DCM as the gradient to afford the title compound.
Reaction SMILES: [N+](C1C=CC([O:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=O)=CC=1)([O-])=O.O.[NH2:20][NH2:21]>CO>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[NH:11][C:9](=[O:8])[NH:20][NH2:21]
Reactant: O=C(Nc1nccs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)Nc1nccs1

Procedure:
A solution of 2-(4-nitrophenoxycarbonyl)aminothiazole, 3.5 g (13 mMole) and 85% hydrazine hydrate, 4.0 ml (69 mMole) in 40 ml of methanol was stirred under nitrogen at 22° C. for 10 days. The mixture was cooled in ice. The insolubles were filtered, washed with cold methanol, dried and recrystallized from ethanol furnishing 780 mg of (thiazol-2-yl)semicarbazide, m.p. 166°-167° C., which was characterized by nuclear magnetic resonance, mass spectra, infrared spectra and elemental analyses.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13]I.O>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1ccc(C=CC(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.7 %

Procedure:
To a solution of 3-(4-methylphenyl)-2-propenoic acid (10.0 g, 61.7 mmol) in THF (100 ml) were added 1,4-diazabicyclo[5.4.0]-7-undecene (11.0 mL, 73.6 mmol) and methyl iodide (4.3 mL, 69.1 mmol) under ice cooling and the mixture was stirred at room temperature for 24 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium sulfite, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane to obtain 9.10 g (yield 84%) of the title compound. mp. 56–58° C.
Reaction SMILES: [CH2:1]([O:5][C:6](Cl)=[O:7])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][C:23]2[N:27]=[C:26]([C:28]3[O:36][C:35]4[CH:34]=[CH:33][N:32]=[C:31]([C:37]#[N:38])[C:30]=4[CH:29]=3)[O:25][N:24]=2)[CH2:18][CH2:17]1>C(Cl)Cl.CCOCC.O>[CH2:1]([O:5][C:6]([N:16]1[CH2:17][CH2:18][CH:19]([CH2:22][C:23]2[N:27]=[C:26]([C:28]3[O:36][C:35]4[CH:34]=[CH:33][N:32]=[C:31]([C:37]#[N:38])[C:30]=4[CH:29]=3)[O:25][N:24]=2)[CH2:20][CH2:21]1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: N#Cc1nccc2oc(-c3nc(CC4CCNCC4)no3)cc12
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)COC(=O)N1CCC(Cc2noc(-c3cc4c(C#N)nccc4o3)n2)CC1
Reaction time: 0.5 h

Procedure:
i-BuOCOCl (19 μL, 146 μmol) and NEt3 (15 μL, 107 μmol) were added to a stirred solution of 2-(3-piperidin-4-ylmethyl-[1,2,4]oxadiazol-5-yl)furo[3,2-c]pyridine-4-carbonitrile (Preparation 15, 30 mg, 97 μmol) in anhydrous CH2Cl2 (1.5 mL). After 30 min, the reaction mixture was diluted with Et2O (10 mL) and H2O (2 mL). The organic layer was washed with saturated aqueous Na2CO3 (2 mL), H2O (2 mL), and brine (2 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (EtOAc) furnished the title compound: RT=3.95 min; m/z (ES+)=410.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH2:13][CH3:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH3:3].[OH:15]O>[Pt]>[CH2:12]([N+:4]([O-:15])([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:13][CH3:14]
Reactant: OO
Reactant: CCCN(CCC)CCCCCCO
Agent: [Pt]
Product: CCC[N+]([O-])(CCC)CCCCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.2 %

Procedure:
To 44 g of dipropyl-6-hydroxyhexyl amine was added slowly 11.0 g of 30% hydrogen peroxide. After stirring overnight at room temperature, the reaction mixture was stirred with 0.2 platinum black for several hours followed by filtration through Hyflo® filter-aid. After extraction with 50 ml ether, the aqueous phase was evaporated in vacuo to remove most of the water, leaving 2.0 g of dipropyl-6-hydroxyhexyl amine oxide. NMR analysis showed that there was 30% water present.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:20]([O-])=O)[CH:15]=3)[N:10]=2)=[CH:4][C:3]=1[CH3:23]>CN(C)C=O.[Pd]>[NH2:20][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([OH:1])=[C:3]([CH3:23])[CH:4]=1)[NH:18][C:17]2=[O:19]
Reactant: Cc1cc(-c2nc3ccc([N+](=O)[O-])cc3c(=O)[nH]2)cc(C)c1O
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccc(N)cc3c(=O)[nH]2)cc(C)c1O
Yield: 66.1 %

Procedure:
To a round-bottomed flask were added 2-amino-5-nitro-benzamide (0.681 g, 3.76 mmol), 4-hydroxy-3,5-dimethyl-benzaldehyde (0.565 g, 3.76 mmol), sodium bisulfite (0.747 g, 4.2 mmol), p-toluenesulfonic acid, monohydrate (0.072 g, 0.376 mmol) and N,N-dimethylacetamide (60 mL). The reaction mixture was refluxed at 155° C. for 16 h before being cooled to room temperature. Water was added and the precipitated solid was filtered off, washed with water and methanol to obtain a crude which was purified by column chromatography (silica gel (50 g) employing 1-20% methanol in dichloromethane as eluents, to obtain 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 19%). The compound 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 0.71 mmol) was hydrogenated in dimethyl formamide (20 mL) using palladium on activated carbon (0.076 g, 0.071 mmol) at room temperature for 14 h. The solvent was evaporated and the crude was purified by column chromatography (silica gel 25 g) employing 1-5% methanol in dichloromethane as eluents to obtain 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one (0.132 g). The compound 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one was dissolved in pyridine under nitrogen. Acetic anhydride was added at room temperature and stirred for 4 h. Pyridine was removed and the residue was dried. Methanol was added to the flask and a solution of potassium carbonate in water was added and stirred for 4 h. The solvent was removed, acidified with 1 N hydrochloric acid and the precipitated solid was filtered off and dried to obtain N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide (0.037 g, 17%). Selected data: MS (ES) m/z: 324.1; MP 336.5° C. (decomposed).
Reaction SMILES: [Cl-].[C:2]([C:5]1[CH:17]=[CH:16][C:8]([CH2:9][NH+:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=1)(O)=[O:3].CN(C=O)C.S(Cl)([Cl:25])=O>C1(C)C=CC=CC=1>[N:10]1([CH2:9][C:8]2[CH:16]=[CH:17][C:5]([C:2]([Cl:25])=[O:3])=[CH:6][CH:7]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=C(O)c1ccc(C[NH+]2CCOCC2)cc1
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(CN2CCOCC2)cc1
Temperature: 70 °C

Procedure:
A 200 mL round-bottom flask fitted with a reflux condenser was charged with 4-(4-carboxy-benzyl)-morpholin-4-ium chloride (10.0 g, 0.039 mol, 1.0 eq), toluene (50 mL), DMF (0.3 mL, 0.0039 mol, 0.1 eq), and thionyl chloride (7.1 mL, 0.097 mol, 2.5 eq) under a nitrogen atmosphere. The reaction mixture was heated to 70° C. for 6 h and then cooled to 0° C. The resulting mixture was filtered and the solid washed with pentane to yield 4-morpholin-4-ylmethyl-benzoyl chloride, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[CH:12][CH:13]([CH3:15])[CH3:14])[NH:8][C:5]2=[N:6][CH:7]=1>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH:11]([C:16]3[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][CH:21]=3)[CH2:12][CH:13]([CH3:15])[CH3:14])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)C=C(c1ccc(S(C)(=O)=O)cc1)c1cc2cc(F)cnc2[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(c1ccc(S(C)(=O)=O)cc1)c1cc2cc(F)cnc2[nH]1
Temperature: 50 °C
Yield: 63.1 %

Procedure:
A mixture of 5-fluoro-2-[1-(4-methanesulfonyl-phenyl)-3-methyl-but-1-enyl]-1H-pyrrolo[2,3-b]pyridine (600 mg, 1.67 mmol) and 10% palladium on activated carbon (180 mg) in methanol (300 mL) was heated at 50° C. under hydrogen (50 psi) for 6 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 5-fluoro-2-[1-(4-methanesulfonyl-phenyl)-3-methyl-butyl]-1H-pyrrolo[2,3-b]pyridine (380 mg, 63%) as a white solid: LC/MS m/e calcd for C19H21FN2O2S [M+H]+ 361.45, observed 361.0; 1H NMR (400 MHz, CDCl3) δ ppm 11.77 (br. s., 1H), 8.16 (br. s., 1H), 7.97-8.01 (m, 1H), 7.90 (d, J=8.1 Hz, 2H), 7.52-7.60 (m, 2H), 6.52 (s, 1H), 4.45 (t, J=7.8 Hz, 1H), 3.03-3.07 (m, 3H), 1.98-2.16 (m, 2H), 1.50 (dt, J=13.5, 6.6 Hz, 1H), 0.95-1.02 (m, 6H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1)(=O)C.C[Si](C)(C)[C:15]#[CH:16]>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.[Cu]I.C(N(CC)CC)C>[C:15]([C:8]1[N:7]=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][CH:9]=1)#[CH:16]
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)OCc1cccc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C#Cc1cccc(CO)n1
Reaction time: 1 h
Yield: 15.9 %

Procedure:
To a round-bottom flask was added 2.3 g of 6-bromopyridin-2-ylmethyl acetate, 1.18 g of trimethyl silylacetylene, 210 mg of bis(triphenylphosphine)-palladium(II) chloride, 114 mg of copper(I) iodide and 12 mL of triethylamine, and then the mixture was heated to reflux under argon atmosphere for 5 hours. After allowing to cool, the mixture was concentrated to dryness under reduced pressure, thereto water was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, 7 mL of methanol and 30 mL of 1N aqueous potassium hydroxide were added to the residue, and the mixture was stirred for 1 hour. The reaction mixture was acidified with 1N hydrochloric acid and concentrated under reduced pressure. The concentrated solution was basified with potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed off under reduced pressure. The product was purified by chromatography on silica gel (hexane-ethyl acetate=4:1) to give 212 mg of (6-ethynylpyridin-2-yl)methanol as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[NH:7][CH2:8][CH:9]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]=1[CH3:45])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:48]1[N:55]=[CH:54][CH:53]=[CH:52][C:49]=1[CH:50]=[O:51]>>[Cl:29][C:22]1[CH:23]=[C:24]([CH3:28])[CH:25]=[C:26]([Cl:27])[C:21]=1[O:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:9]([C:30]2[CH:35]=[CH:34][C:33]([C:48]3[C:49]([CH:50]=[O:51])=[CH:52][CH:53]=[CH:54][N:55]=3)=[CH:32][C:31]=2[CH3:45])[CH2:8][NH:7][C:6](=[O:46])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:12][CH:13]=1
Reactant: O=Cc1cccnc1Br
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(-c4ncccc4C=O)cc3C)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl{3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and commercially available 2-bromonicotinaldehyde as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 75% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:11]([Cl:13])=[CH:10][CH:9]=[C:8]3[C:14](=[O:17])[CH2:15][CH2:16][C:6]([C:7]=23)=[CH:5]1)(=[O:3])[CH3:2].C1C=C[NH+]=CC=1.[Br:24][Br-]Br.O>C(O)(=O)C>[C:1]([N:4]1[C:12]2[C:11]([Cl:13])=[CH:10][CH:9]=[C:8]3[C:14](=[O:17])[CH:15]([Br:24])[CH2:16][C:6]([C:7]=23)=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1cc2c3c(ccc(Cl)c31)C(=O)CC2
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)n1cc2c3c(ccc(Cl)c31)C(=O)C(Br)C2
Reaction time: 3.5 h

Procedure:
To a stirred mixture of 1-acetyl-8-chloro-3,4-dihydrobenz[cd]-indol-5(1H)-one (9.7 g, 0.04 mole) in acetic acid (80 ml.) is added in one portion pyridinium bromide perbromide (13.8 g., 0.042 mole). The stirring is continued for 3.5 hours and then water (150 ml.) is added to the reaction mixture. The dark solid that separates is recovered by filtration and dried. The crude yield is 10 g. (89%) of material that is used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:14](=[O:16])[NH:13][N:12]=[C:11]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:10]=3[S:9][CH:8]=2)=[CH:3][CH:2]=1.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH2:33][CH2:34]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:34][CH2:33][C:24]4[CH:25]=[CH:26][C:27]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:23]=4)[N:12]=[C:11]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:10]=3[S:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: OCCc1ccc2ccccc2n1
Reactant: O=c1[nH]nc(-c2ccncc2)c2scc(-c3ccncc3)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1c2c(-c3ccncc3)csc2c(-c2ccncc2)nn1CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.6 %

Procedure:
To a solution of 3,7-di(pyridin-4-yl)thieno[2,3-d]pyridazin-4(5H)-one from example 1.5 (100 mg, 0.32 mmol), 2-quinolin-2-yl-ethanol from example a1 (58 mg, 0.33 mmol) and PPh3 (256 mg, 0.98 mmol) in DCM (10 mL), DIAD (198 mg, 0.98 mmol) was added dropwise. The mixture was stirred at room temperature for 3 h, concentrated and the residue was purified by Prep-HPLC to give the title compound as white solid (26 mg, 17.6% yield).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:29])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][C:20]=3[O:27][CH3:28])[N:16]=2)[CH:7]=1)(=[O:4])=[O:3].[OH:30][C:31]1[C:35]([CH:36]=[O:37])=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:29])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:30][C:31]4[C:35]([CH:36]=[O:37])=[CH:34][N:33]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:32]=4)=[CH:21][C:20]=3[O:27][CH3:28])[N:16]=2)[CH:7]=1)(=[O:4])=[O:3]
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
To a mixture of 3-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate (2.00 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.81 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.19 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate as colorless crystals (1.43 g, yield 56%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 146-148° C.
Reaction SMILES: [C:1]([CH:3]([CH:9]([CH3:26])[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:25])/[CH2:14][CH2:15]/[CH:16]=[C:17](\[CH3:24])/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])C(OCC)=O)#[N:2].[OH-].[Na+].C(O)C(O)C.Cl>>[CH3:26][CH:9]([CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:25])/[CH2:14][CH2:15]/[CH:16]=[C:17](\[CH3:24])/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH2:3][C:1]#[N:2]
Reactant: CCOC(=O)C(C#N)C(C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(O)CO
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(C)CC#N

Procedure:
To the entirety of the product obtained in the above (a) step, there were added 29 g. of sodium hydroxide and 100 ml. of propylene glycol, and the mixture was stirred at room temperature for 10 min. The reaction mixture was made acidic by addition of 6N hydrochloric acid, and was then extracted with benzene. The extract was then washed with water and dried. The solvent was then removed by evaporation. The obtained oily product was dissolved in 100 ml. of pyridine, and the resulting solution was refluxed for 2 hours after addition of 0.5 g. of copper powder. Subsequently, the copper powder was removed by filtration and the solvent was removed by evaporation. The residue was dissolved in n-hexane, washed with water and dried. The solvent was then removed by evaporation and the residue was purified by silica gel column chromatography to obtain 34 g. of the desired oily product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH3:12])=[O:10].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([S:30]([O-:32])=[O:31])[CH:24]=[CH:23]3)=[CH:16][CH:15]=1.[Na+]>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([S:30]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9]([NH:11][CH3:12])=[O:10])(=[O:32])=[O:31])[CH:24]=[CH:23]3)=[CH:16][CH:15]=1
Reactant: CNC(=O)Nc1ccccc1I
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Product: CNC(=O)Nc1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1

Procedure:
Prepared according to the method of Example 6 Step 4 using N-(2-iodophenyl)-N′-methylurea and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate, to give the title compound as a white solid (81 mg). 1H NMR (500 MHz, d6-DMSO): δ 8.81 (1H, s), 8.34 (2H, s), 8.18 (2H, dd, J=8.6, 21.9 Hz), 8.08-8.02 (2H, m), 7.97 (1H, d, J=8.3 Hz), 7.90 (2H, dd, J=5.5, 8.7 Hz), 7.84 (1H, dd, J=1.7, 8.6 Hz), 7.61-7.57 (1H, m), 7.52 (1H, s), 7.37 (2H, t, J=8.8 Hz), 7.25 (1H, t, J=7.6 Hz), 2.56 (3H, d, J=4.4 Hz); m/z (ES+) 411 [MH+].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[O:19]=[C:20]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:35][C:22]2([CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH2:21]1.[CH:42](=[O:44])[CH3:43]>C1COCC1>[OH:44][CH:42]([CH:21]1[C:22]2([CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)[O:35][C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:20]1=[O:19])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 63.2 %

Procedure:
To a solution of N-isopropylpropan-2-amine (0.57 mL, 4.1 mmol) in THF (3.5 mL) was added a solution of n-butyllithium in hexane (2.6 mL of 1.6 M, 4.1 mmol) dropwise at −78° C. under Ar. The solution was allowed to stir at −20° C. for 15 min and then cooled to −78° C. tert-Butyl 4-oxospiro[chromane-2,4′-piperidine]-1′-carboxylate (1.1 g, 3.5 mmol) in THF (3.5 mL) was added at −78° C. followed by the addition of acetaldehyde (0.22 mL, 3.9 mmol) in THF (3 mL). The reaction was quenched with saturated aqueous ammonium chloride at −78° C., warmed to 25° C. and extracted with ethyl acatate (2×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to dryness. Purification by silica gel chromatography (20-30% ethyl acetate in hexane) provided tert-butyl 3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (0.80 g, 63%) as a colorless oil. ESI-MS m/z calc. 361.2, found 362.5 (M+1)+; Retention time: 1.79 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J=7.8, 1.6 Hz, 1H), 7.55-7.48 (m, 1H), 7.06-6.96 (m, 2H), 4.33-4.23 (m, 1H), 4.10-3.93 (m, 1H), 3.88-3.67 (m, 1H), 3.41-3.27 (m, 1H), 3.07-2.94 (m, 1H), 2.62 (d, J=5.2 Hz, 1H), 2.45 (d, J=8.5 Hz, 1H), 2.20-2.00 (m, 2H), 1.85-1.76 (m, 1H), 1.58-1.49 (m, 1H), 1.46 (s, 9H), 1.26 (t, J=7.1 Hz, 1H) 1.13 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1([CH3:24])[C:16]2[C:11](=[CH:12][C:13]([C:17](=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=2)[S:10][CH2:9][CH2:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][C:7]1([CH3:24])[C:16]2[C:11](=[CH:12][C:13]([C:17](=[CH2:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=2)[S:10][CH2:9][CH2:8]1
Reactant: CCCCCC(=O)c1ccc2c(c1)SCCC2(C)C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(CCCCC)c1ccc2c(c1)SCCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of methyl triphenylphosphonium bromide (2.293 g, 6.42 mmole) in 40 mL of THF at 0° C., was treated dropwise with 2.6 mL of 2.5M butyllithium. The mixture was stirred at room temperature for 30 minutes and then cooled to 0° C. A solution of 1-(4,4-dimethyl-thiochroman-7-yl)-hexan-1-one (1.183 g, 4.28 mmole) in 10 mL of THF was added to the ylide solution. The reaction mixture was stirred at room temperature for one hour, quenched by the addition of 50 mL water and was extracted with three 50 mL portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid. The product was purified by flash chromatography (SiO2, 1% ethyl acetate in hexanes) to yield 0.939 g of 4,4-dimethyl-7-(1-methylene-hexyl)-thiochroman as a colorless oil.