Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([CH3:15])[O:14][CH2:13][CH2:12][CH2:11][O:10]1.[H-].C([Al+]CC(C)C)C(C)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([O:10][CH2:11][CH2:12][CH2:13][OH:14])[CH3:15]
Reactant: COc1ccccc1C1(C)OCCCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1C(C)OCCCO

Procedure:
The solution of 61.9 g of 2-(2-methoxyphenyl)-2-methyl-[1,3]dioxane in 450 ml of toluene is cooled to 0° C. with stirring and admixed at 0-10° C. with 487 ml of diisobutylaluminum hydride (1.5M in toluene) over 1 hour. The mixture is stirred over 2.5 hours and subsequently poured onto the stirred solution of 382 g of citric acid monohydrate in 2 l of water. The organic phase is removed and the water phase extracted with tert-butyl methyl ether (1 l). The organic phases are washed with brine (1 l), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.12 (1:2 EtOAc-heptane); Rt=3.56.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][N:10]([CH3:12])[CH3:11])[S:7][CH:8]=1.Cl.[NH2:14][CH2:15][CH2:16][SH:17].O.[OH-].[Na+]>ClCCl>[NH2:14][CH2:15][CH2:16][S:17][CH2:3][C:4]1[N:5]=[C:6]([CH2:9][N:10]([CH3:12])[CH3:11])[S:7][CH:8]=1
Reactant: CN(C)Cc1nc(CCl)cs1
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN(C)Cc1nc(CSCCN)cs1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To the aqueous phase from Example 14 above was added 27 g. of 2-aminoethanethiol, hydrochloride. The mixture was heated and stirred, until the pot temperature reached 120°. The mixture was held at that temperature for 6 hours, and was then allowed to cool to 60°. To the residue was added 80 ml. of deionized water, and the mixture was allowed to cool to ambient temperature and stand for some days. Eighty ml. of dichloromethane was then added, and the pH of the mixture was adjusted to 6.1 by the addition of 9 ml. of 50% sodium hydroxide. The aqueous layer was extracted twice with 40 ml. portions of dichloromethane, and the aqueous layer was then mixed with 80 ml. of dichloromethane and the pH was adjusted to 12.6 by the addition of 40 ml. of 50% sodium hydroxide. The aqueous layer of the resulting mixture was extracted twice with 40 ml. of dichloromethane, and the two aqueous layers were combined, filtered and evaporated under vacuum to obtain 31.5 g. of the desired product, which was found to be 74.7% pure by the analytical method described in Preparation 1 above.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[OH:21][C:22]1[C:31]2[C:26](=[N:27][C:28]([CH3:32])=[CH:29][CH:30]=2)[N:25]=[CH:24][C:23]=1[C:33](O)=[O:34]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:33]([C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:22]=1[OH:21])=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=2)=[O:34]
Reactant: Cc1ccc2c(O)c(C(=O)O)cnc2n1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: Cc1ccc2c(O)c(C(=O)Nc3ccc(N4CCC(CN5CCCC5C)C4)cc3C)cnc2n1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid. MS: 460.6 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:10][CH2:11][CH3:12])=[O:9]>C(#N)C>[CH2:11]([O:10][C:8](=[O:9])[CH:13]=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH3:12]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)C=C1CCOCC1
Temperature: 70 °C
Yield: 63.5 %

Procedure:
To a solution of tetrahydro-pyran-4-one (25 g, 0.25 mol) in acetonitrile (250 mL) was added (carbethoxymethylene)triphenylphosphorane (96 g, 0.28 mol) at room temperature. The resulting mixture was heated at 70° C. for 16 h. The reaction mixture concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded (tetrahydro-pyran-4-ylidene)-acetic acid ethyl ester (27 g, 63%) as a yellow oil.
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7][CH:6]1CCCC2.Cl[C:26]1[C:27]([O:40][CH2:41][C:42]2([F:48])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH:1]1([C:26]2[C:27]([O:40][CH2:41][C:42]3([F:48])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=2)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(F)CCCCC2)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(F)CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 5-chloro-2-fluoro-4-((1-fluorocyclohexyl)methoxy)benzoate, the title compound was obtained as a colorless gum (1.60 g, 90%): 1H NMR (300 MHz, CDCl3) δ 7.38 (d, J=8.4 Hz, 1H), 6.49 (d, J=12.5 Hz, 1H), 3.93 (d, J=17.8 Hz, 2H), 2.04-1.87 (m, 4H), 1.73-1.55 (m, 6H), 1.54 (s, 9H), 1.36-1.20 (m, 3H), 0.91-0.80 (m, 2H), 0.65-0.57 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[C:45]1([S:51](Cl)(=[O:53])=[O:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[S:51]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=[O:53])=[O:52]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)S(=O)(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and phenylsulfonyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [N:1]12CCC(CC1)C(CO)[CH2:2]2.[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[C:13](=[O:19])[CH2:12]2>>[C:2]([C:13]1([OH:19])[CH:14]2[CH2:17][CH2:18][N:11]([CH2:16][CH2:15]2)[CH2:12]1)#[N:1]
Reactant: O=C1CN2CCC1CC2
Reactant: OCC1CN2CCC1CC2
Product: N#CC1(O)CN2CCC1CC2

Procedure:
A process for the preparation of quinuclidine-3-methanol comprising reacting quinuclidine-3-one acid addition salt with an alkali metal cyanide in an aqueous media to obtain 3-cyano-3-hydroxy-quinuclidine, reacting the latter with anhydrous methanol in the presence of hydrogen chloride gas followed by treatment with aqueous alkali to obtain methyl 3-hydroxy-quinuclidine-3-carboxylate, reacting the latter with thionyl chloride to form methyl 1-azabicyclo(2,2,2)oct-2-ene-3-carboxylate, hydrogenating the latter with Raney nickel to obtain methyl 1-azabicyclo(2,2,2)octane-3-carboxylate and reducing the latter to obtain quinuclidine-3-methanol.
Reaction SMILES: [OH2:1].[Mn]([O-])(=O)(=O)=O.[K+].[CH2:8]([O:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=1[F:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(C)=O>[CH2:8]([O:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][C:19]([C:20]([OH:1])=[O:21])=[CH:18][C:17]=1[F:26])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1cc(C=O)cc(F)c1OCc1ccccc1
Reactant: O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(=O)O)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 200 ml of water and 6.8 g of potassium permanganate was added dropwise 7.5 g of 4-benzyloxy-3-fluoro-5-methoxybenzaldehyde dissolved in 200 ml of acetone at 15 to 20° C., and the resulting mixture was stirred at room temperature for 3 days. Thereafter, the reaction mixture was concentrated under reduced pressure to about half volume. To the concentrated solution were added an aqueous sodium hydrogen sulfite solution and dilute hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure, and 4-benzyloxy-3-fluoro-5-methoxybenzoic acid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[N:8]=2
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4ccnc(C(F)(F)F)c4)cc3)C2=N1
Temperature: 70 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A mixture of 5-chloro-3-(4-(2-(trifluoromethyl)pyridin-4-yloxy)phenyl)pyridin-2-amine (220 mg) in THF (dry) (10 mL) was added to a mixture of NaH (60%, 120 mg) and 2-chloroethanesulfonyl chloride (294 mg) in THF (dry) (10 mL) at room temperature. The mixture was stirred at 70° C. for 1 hr. MeOH and NH silica gel were added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the titled compound (253 mg) as a white solid. The solid was crystallized from CH3CN-IPE to give a white solid.
Reaction SMILES: [CH3:1][CH:2]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([NH2:19])[CH:15]=[CH:14]2)[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].CCN(CC)CC.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>C1COCC1>[CH3:27][C:28]([CH3:33])([CH3:32])[C:29]([NH:19][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[C:9]([O:8][CH:2]([CH3:1])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH:10]=[CH:11][CH:12]=2)[N:17]=1)=[O:30]
Reactant: CC(CC(C)(C)C)Oc1cccc2ccc(N)nc12
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CC(C)(C)C)Oc1cccc2ccc(NC(=O)C(C)(C)C)nc12
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial was added a stir bar, the title compound from Example 16 (161 mg, 0.624 mmol) and 1.5 mL of THF. To the resultant solution was added Et3N (0.174 mL, 2 equiv) and trimethylacetylchloride (93 μL, 1.2 equiv). The solution was allowed to stir overnight, after which time the mixture placed directly on a silica column and eluted with EtOAc/hexanes to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.27 (m, 1H), 7.96–8.18 (m, 1H), 7.42 (m, 2H), 7.21 (m, 1H), 4.64–4.90 (m, 1H), 1.90 (m, 1H), 1.53 (m, 1H), 1.31 (m, 12H), 0.83–1.05 (m, 9H); MS (DCI/NH3) m/z 343 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:10])[N:3]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[N:4]1.[Br:11][C:12]1[CH:17]=[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:15](I)=[CH:14][N:13]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]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>[Br:11][C:12]1[N:13]=[CH:14][C:15]2[CH:9]=[C:8]([C:6]3[CH:5]=[N:4][N:3]([CH:2]([F:10])[F:1])[CH:7]=3)[N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[C:16]=2[CH:17]=1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Reactant: C#Cc1cnn(C(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1c(-c2cnn(C(F)F)c2)cc2cnc(Br)cc21
Temperature: 60 °C
Yield: 34.3 %

Procedure:
1-(Difluoromethyl)-4-ethynyl-1H-pyrazole (Preparation 152, 187 mg 1.31 mmole) was dissolved in DMF (4.2 mL) and N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide (Preparation 8, 444 mg 1.17 mmole) was added. To the solution was added triethylamine (0.80 mL, 576 mg 5.7 mmole) and copper(I) iodide (9 mg 0.047 mmole). The reaction was sealed and flushed with nitrogen. Bis(triphenylphosphine)palladium dichloride (37.6 mg 0.046 mmole) was added and the reaction was again flushed with nitrogen, then heated at 60° C. for 140 minutes. The reaction was added to ethyl acetate (45 mL) and washed with water (3×15 mL) and with brine, then dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with 5% ethyl acetate in chloroform to afford the title compound 157 mg. 1H-NMR (d6-acetone, 500 MHz): δ 3.37 (s, 3H), 7.06 (d, J=0.63 Hz, 1H), 7.70 (t, J=59.6 Hz, 1H), 8.04 (s, 1H), 8.16 (m, 1H), 8.51 (s, 1H), 8.73 (d, J=0.95 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][CH:29]([N:31]=[C:32]=[O:33])[CH3:30].O>ClCCl>[CH:29]([NH:31][C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1)=[O:33])([CH3:30])[CH3:28]
Reactant: CC(C)N=C=O
Reactant: CN(Cc1cccc(-c2ccc(N)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)NC(=O)Nc1ccc(-c2cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To an ice-cooled solution of tert-butyl (2-{[(4′-aminobiphenyl-3-yl)methyl](methyl)amino]-2-oxoethyl}carbamate (200 mg) in dichloromethane (4 ml) was added 2-propyl isocyanate (55 mg), followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by stirring, and the organic layer was purified by silica gel column chromatography (2% MeOH/CHCl3) to obtain tert-butyl {2-[({4′-[(isopropylcarbamoyl)amino]biphenyl-3-yl}methyl)(methyl)amino]-2-oxoethyl}carbamate (240 mg) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.I[CH3:23]>>[CH3:23][O:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COC(=O)CCc1ccc(C#Cc2cccc(O)c2)cc1
Product: COC(=O)CCc1ccc(C#Cc2cccc(OC)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-((3-hydroxyphenyl)ethynyl)phenyl)propanoate (41 mg, 0.20 mol) and iodomethane (60 μL, 0.97 mmol) according to the general procedure IV to give 38 mg (69%) of a pure yellow oil. Rf=0.37 (EtOAc:PE, 1:3); 1H NMR (CDCl3): δ 7.45 (dt, J=8.3 Hz, 2.0 Hz, 2H), 7.27-7.23 (m, 1H), 7.18 (d, J=8.3 Hz, 2H), 7.12 (dt, J=7.5 Hz, 1.3 Hz, 1H), 7.05 (dd, J=2.8 Hz, 1.5 Hz, 1H), 6.88 (ddd, J=8.4 Hz, 2.4 Hz, 1.0 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 2.63 (t, J=7.8 Hz, 2H); 13C NMR (CDCl3): δ 173.1, 159.3, 140.9, 131.8, 129.4, 128.3, 124.3, 124.1, 121.1, 116.3, 114.8, 89.1, 89.0, 55.3, 51.6, 35.4, 30.8.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1c(O)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2′,6′-dihydroxyacetophenone (4 g) and potassium carbonate (3.82 g) in acetone (40 mL) was added benzyl bromide (3.13 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration. The crystals were washed with water and n-hexane, and dried under reduced pressure to give the title compound (3.67 g).
Reaction SMILES: C1COCC1.[NH:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.C1C=CC2N(O)N=NC=2C=1.[NH:32]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:33]([C:43](O)=[O:44])[CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[NH:32]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:33]([C:43]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:44])[CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
THF (100 ml, H-Pro-OBzl.HCl (31.5 g, 0.13 M) and HOBT (17.5 g, 0.13 M) were added to BOC-Ser(Bzl)-OH (35.4 g, 0.12 M), and then DMF (50 ml) was added thereto to prepare a solution. WSCI (24.8 ml) was added dropwise and stirred at 0° C. for one hour and then at room temperature overnight. The solvent was distilled off in vacuo and benzene was added to the residue, which was then washed three times with 5% sodium bicarbonate solution, three times with 1 N HCl and three times with water, in that order. After drying with anhydrous sodium sulfate, the solution was dried in vacuo to obtain the substance [17] as an oil material (58 g, yield: 100%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH3:15])=[N+:12]([O-])[CH:13]=1)#[N:7].C(N(CC)CC)C>ClCCl>[Cl:3][CH2:15][C:11]1[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][N:12]=1
Reactant: Cc1ccc(C#N)c[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CCl)nc1

Procedure:
A solution of phosphoryl chloride (6.5 g) in dichloromethane (20 ml) was added to a mixture of the above pyridine-1-oxide (4.4 g) and triethylamine (4.3 g) in dichloromethane (60 ml). After the addition was completed the reaction mixture was gently refluxed for 15 mins, cooled and washed with water (30 ml). The organic layer was separated, dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by flash column chromatography on silica (K60) using ethyl acetate: toluene (1:9 by volume) as eluting solvent, to give 6-chloromethylnicotinonitrile.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:18]([F:19])=[C:17]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([OH:21])=[C:14]([F:20])[C:15]=3[CH2:16]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[C:15](=[C:14]([F:20])[C:13]([O:21][CH2:23][CH2:24][CH3:25])=[CH:12][CH:11]=3)[CH2:16][C:17]=2[C:18]=1[F:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1F)Cc1c-2ccc(O)c1F
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc2c(c1F)Cc1c-2ccc(OCCC)c1F

Procedure:
The etherification of 9 mmol of 7-butoxy-1,8-difluorofluoren-2-ol with 12 mmol of 1-bromopropane and 27 mmol of potassium carbonate in 50 ml of acetone is effected in a similar manner to the procedure described in Example 1. Purification of the crude product by chromatography on silica gel (dichloromethane/heptane) and recrystallization from heptane provides 2-butoxy-1,8-difluoro-7-propyloxyfluorene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([NH2:13])[N:10]([CH3:14])[N:9]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([NH:13][C:15](=[O:17])[CH3:16])[N:10]([CH3:14])[N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc(-c2ccccc2Cl)cc1N
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-c2ccccc2Cl)nn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.2 %

Procedure:
To a solution of 3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-amine (617 mg, 3 mmol) in pyridine (6 mL) was added acetic anhydride (425 μl, 4.5 mmol). The reaction was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, gradient 0 to 100% ethyl acetate/isohexane) yielding N-(3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)acetamide as a solid (526 mg).
Reaction SMILES: [C@@H:1]1([CH2:7][C:8]#[N:9])[CH2:3][C@H:2]1[CH2:4][C:5]#[N:6].N[NH:11][C:12]([NH2:14])=[S:13]>C(O)(C(F)(F)F)=O>[C@@H:1]1([CH2:7][C:8]2[S:13][C:12]([NH2:14])=[N:11][N:9]=2)[CH2:3][C@H:2]1[CH2:4][C:5]1[S:13][C:12]([NH2:14])=[N:11][N:6]=1
Reactant: N#CC[C@@H]1C[C@H]1CC#N
Reactant: NNC(N)=S
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(C[C@@H]2C[C@H]2Cc2nnc(N)s2)s1
Temperature: 100 °C

Procedure:
trans-2,2′-(cyclopropane-1,2-diyl)diacetonitrile I-4 (1 equivalent) was dissolved in TFA (2.0 mL) and thiosemicarbazide (2 equivalents) was added to it. The reaction mixture was refluxed for 3 h at 100° C. before quenching by careful addition of a saturated solution of NaHCO3 at 0° C. to bring the pH around 8-9. The solid precipitated was filtered and further purified to obtain trans-5,5′-(-cyclopropane-1,2-diylbis(methylene))bis(1,3,4thiadiazol2-amine) I-5.
Reaction SMILES: C([O:4][C:5]1[C:6]2[N:7]([C:11]([Br:15])=[C:12]([CH3:14])[N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=O)C.[OH-].[Na+].Cl>CO>[Br:15][C:11]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:5]([OH:4])[C:6]2=[N:13][C:12]=1[CH3:14]
Reactant: CC(=O)Oc1cccn2c(Br)c(C)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2c(O)cccn2c1Br
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of 8 -acetoxy-3-bromo-2-methylimidazo[1,2-a]pyridine (235 mg) in methanol (2.5 ml) was added 1N sodium hydroxide solution (2.0 ml) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. The mixture was neutralized with 1N hydrochloric acid, and the resulting precipitates were collected by filtration and washed with water to give 3-bromo-8-hydroxy-2-methylimidazo[1,2-a]pyridine (150 mg) as brown powder.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.Cl[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15].O>CN(C)C=O>[Br:3][C:4]1[C:9]([O:10][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(C)=CCCl
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCOc1cccnc1Br
Yield: 86 %

Procedure:
Sodium hydride (160 mg) was dissolved in dimethylformamide (5 ml) and 2-bromo-3-pyridinol (500 mg) dissolved in dimethylformamide is slowly added dropwise. Then, 1-chloro-3-methyl-2-butene (0.63 ml) was added to the solution and reacted for 5 hours at room temperature. Water was added to the suspension to dilute and extracted with ethyl acetate to separate an organic layer. The separated organic layer was dried with anhydrous magnesium sulfate and distilled under reduced pressure. As a result, 2-bromo-3-(3-methyl-2-butenyloxy)-pyridine (600 mg, yield: 86%) was obtained as an oil phase.