Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([CH3:22])[S:19][C:17]=2[N:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:21]=[C:20]([CH3:22])[S:19][C:17]=2[N:18]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: Cc1cc2c(Cl)nc(Cl)nc2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.4 %

Procedure:
3.02 g of 3,4-methylenedioxybenzylamine ("A") are added to a solution of 3.29 g of 2,4-dichloro-6-methylthieno-[2,3-d]-pyrimidine in 80 ml of methylene chloride and, after addition of 1.52 g of triethylamine, the mixture is stirred at room temperature for 12 hours. The solvent is removed and the residue is worked up in the customary manner. 3.38 g of 2-chloro-6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine are obtained, m.p. 162°.
Reaction SMILES: [OH-].[Na+].CO.C[O:6][C:7](=[O:26])[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15]/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=2)=[CH:10][CH:9]=1.Cl>O.O1CCOCC1>[CH:24]([C:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([OH:26])=[O:6])=[CH:13][CH:12]=2)=[CH:23][CH:22]=1)=[O:25]
Reactant: COC(=O)c1ccc(C#C/C=C/c2ccc(C=O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc(/C=C/C#Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A 20% aqueous solution (1.5 mL) of sodium hydroxide was added to a methanol (20 mL)-1,4-dioxane (20 mL) solution of 4-[(E)-4-(4-formylphenyl)but-3-en-1-yn-1-yl)benzoic acid methyl ester (0.59 g) as obtained in Example 23-(1), and then the mixture was stirred for 3 hours at room temperature. A 20% aqueous solution (1.5 mL) of sodium hydroxide was added, and the mixture was stirred for 30 minutes at room temperature. Water was added, and the mixture was adjusted to pH 3 with 12 mol/L hydrochloric acid. The precipitate was filtered off to obtain 4-[(E)-4-(4-formylphenyl)but-3-en-1-yn-1-yl)benzoic acid (orange solid) (0.55 g, 98%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>>[CH:21]1([C:24]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:25])[CH2:23][CH2:22]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)C1CC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate and cyclopropanecarboxylic acid chloride, there is obtained ethyl N-cyclopropylcarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 97°-99° C.;
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:17]([C@@H:24]1[CH2:29][C@@H:28]([N:30]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][CH:39]=2)[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH2:27][CH2:26][NH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(Cl)Cl>[CH2:17]([C@@H:24]1[CH2:29][C@@H:28]([N:30]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][CH:39]=2)[C:31](=[O:36])[C:32]([F:34])([F:35])[F:33])[CH2:27][CH2:26][N:25]1[C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reaction time: 3 h

Procedure:
72 μl (0.515 mmol) of triethylamine and 54 μl (0.468 mmol) of benzoyl chloride are added to a solution of 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine in 4 ml of methylene chloride. The reaction mixture is stirred at 0° for 3 hours, water is added, extraction with methylene chloride is carried out. The organic phases are dried over magnesium sulfate and evaporated to dryness. The yellow oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (1000:50:1). The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.72, FD-MS: M+ =531.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(O)(=O)[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].CC#N.O>[N+]([O-])([O-])=O.[Ag+].C(OCC)(=O)C>[C:18]([CH2:17][CH2:16][CH2:15][C:11]1[C:10](=[O:12])[C:9]2[C:4]([C:3](=[O:13])[C:2]=1[CH3:1])=[CH:5][CH:6]=[CH:7][CH:8]=2)([OH:20])=[O:19]
Reactant: CC1=CC(=O)c2ccccc2C1=O
Reactant: O=C(O)CCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1=C(CCCC(=O)O)C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
The CPVK3 was synthesized referring to a document (Salmon-Chemin L., Buisine E., Yardley V., Kohler S., Debreu M. A., Landry V., Sergheraert C., Croft S. L., Krauth-Siegel R. L., and Davioud-Charvet E., J. Med. Chem., 2001, 44, 548-565). 2-methyl-1,4-naphthoquinone, glutaric acid, and AgNO3 were suspended in a 30% aqueous CH3CN solution, heated, and stirred to dissolve completely. Then, a 30% aqueous CH3CN solution of (NH4)2S2O8 was added dropwise in 60 minutes. After completing the dropwise addition, the mixture was stirred at 65° C. for 5 minutes as it was. Cooling of the reaction mixture to room temperature resulted in precipitation of a yellow brown solid. Water and ethyl acetate were added to the reaction mixture, and an organic layer was washed with water using a separating funnel. Further, the organic layer was washed with water. A 2N-aqueous solution of sodium bicarbonate was added to the organic layer, and a sodium salt of a target compound was extracted to an aqueous layer. Then, the aqueous layer was adjusted to a pH of 2 or less using 37% hydrochloric acid, and a precipitated solid was collected by filtration. The solid was sufficiently washed with cool water, and dried under reduced pressure, to thereby obtain a yellow brown powder 2-(3-carboxypropyl)-3-methyl-1,4-naphthoquinone.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:1]([OH:5])(=[O:4])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:11][CH:3]=1.[CH:12](=[O:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCC(=O)O
Reactant: Cc1ccccc1
Product: O=C(O)c1ccccc1
Product: O=Cc1ccccc1
Reaction time: 24 h
Yield: 98 %
Yield: 2 %

Procedure:
The experiment of the preceding example was repeated, while replacing acetic acid with propionic acid. Analysis of the reaction mixture after 24 hours showed that 55% of the toluene employed had been converted mainly to yield benzoic acid (98%) and small quantities of benzaldehyde (2%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][C:38]=1CS(N)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:40]4[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[C:38]([NH:8][S:25]([CH3:28])(=[O:27])=[O:26])[CH:39]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(CCc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 43.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorophenethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.148 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfon amide (Intermediate 17) (58 mg, 0.178 mmol) using sodium carbonate (47 mg, 0.444 mmol) and Pd(PPh3)2Cl2 (5 mg, 0.0074 mmol) in DME/water (10/1 ml). This afforded 27 mg (43.8% yield) after purification by column (Silica gel 60/120) using 30% ethyl acetate in hexane as eluent.
Reaction SMILES: [CH3:1]N(C=O)C.[CH3:6][O:7][C:8](=[O:36])[N:9]=[C:10]([S:34][CH3:35])[C:11]([C:25]1[CH:30]=[C:29]([CH2:31][OH:32])[CH:28]=[C:27]([OH:33])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CI>C(OCC)(=O)C.O>[CH3:6][O:7][C:8](=[O:36])[N:9]=[C:10]([S:34][CH3:35])[C:11]([C:25]1[CH:26]=[C:27]([O:33][CH3:1])[CH:28]=[C:29]([CH2:31][OH:32])[CH:30]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: CN(C)C=O
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(O)cc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(CO)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 3 ml DMF solution containing 700 mg of {2-(3-hydroxy-5-hydroxymethylphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester there was added 440 mg of potassium carbonate and 0.15 ml of methyl iodide, and the mixture was stirred at room temperature for 17 hours and 30 minutes. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (544 mg) as a yellow solid.
Reaction SMILES: [H-].[K+].[NH2:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][C:6]([OH:14])([CH2:7]3)[CH2:5]1)[CH2:11]2.I[CH3:16]>O1CCCC1.C(Cl)Cl>[CH3:16][O:14][C:6]12[CH2:12][CH:10]3[CH2:9][CH:8]([CH2:13][C:4]([NH2:3])([CH2:11]3)[CH2:5]1)[CH2:7]2
Reactant: CI
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC12CC3CC(CC(N)(C3)C1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred, ice-water chilled suspension of potassium hydride (0.680 gm; 5.95 mmol) in 15.0 ml of tetrahydofuran is added a mixture of 1-aminoadamantane-3-ol (1.00 g; 5.95 mmol) and 15.0 ml of tetrahydrofuran dropwise over 30 minutes. The resulting mixture is then stirred for an addition 30 minutes and iodomethane (0.370 ml; 5.95 mmol) is then added dropwise over one minute. The resulting opaque white reaction is then stirred at room temperature for 18 hours. The mixture is then diluted with 50 ml of methylene chloride and filtered to remove the inorganic impurities. The filtrate is then concentrated and purified on silica gel employing a SIMS/Biotage apparatus and 19% methanol and 19% ammonium hydroxide in methylene chloride as eluent to yield 3-methoxy-1-adamantylamine as an opaque oil.
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:22])[C@H:12]2[C@@H:15](OS([O-])(=O)=O)[CH3:16])[C:9]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(=[O:3])[CH3:2].C([N+](C)(C)CCCCCCCCCCCCCCCC)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:22])/[C:12]/2=[CH:15]\[CH3:16])[C:9]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(=[O:3])[CH3:2].[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:22])/[C:12]/2=[CH:15]/[CH3:16])[C:9]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@H](C)OS(=O)(=O)[O-])[C@H]2C1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C/C=C1/C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S/C=C/NC(C)=O)C[C@H]12
Product: C/C=C1\C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S/C=C/NC(C)=O)C[C@H]12
Reaction time: 3.5 h
Yield: 102732.4 %

Procedure:
Benzyldimethyl-n-hexadecylammonium (5R,6R)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-sulphonatooxyethyl]-7-oxo-2-p-nitrobenzyloxycarbonyl-1-azabicyclo[3.2.0]hept-2-ene (e46) (1.85 mg) was dissolved in methylene chloride (40 ml) and the solution cooled to -15°. A solution of DBU (0.634 g) in methylene chloride (10 ml) was added, and stirring was continued at -10° for 3.5 hours. The organic solution was washed with 3 portions of brine (20 ml), then dried (MgSO4) and evaporated. The residue was chromatographed on silica gel eluting first with petrol/ethyl acetate (1:4) and then with ethyl acetate to yield p-nitrobenzyl (5R,6Z)-3-[(E)-2-acetamidoethenylthio]-6-ethylidene-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate and p-nitrobenzyl (5R,6E)-3-[(E)-2-acetamidoethenylthio]-6-ethylidene-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e3 and e6) (0.46 g) in which the E- to Z-isomer ratio was about 1:1.2. Trituration of the mixed products under ethyl acetate gave a pale yellow solid; (Found; C, 55.8; H, 4.5, N, 9.7%, M+, 429.0999. C20H19N3O6S requires C, 55.9; H, 4.5; N, 9.8%, M+ 429.0994). νmax (KBr) 1760, 1690 and 1620 cm-1 ; λmax (EtOH) 340sh (11,000), 310 (13,400) and 268 nm (17,400); δ (DMF-d7) 1.82 and 2.00 (Total 3H, each d, J 7 Hz, CH3CH for E- and Z-isomer, respectively), ca. 1.98 (3H, s, CH3CO), ca. 3.2 (2H, m, CH2C.S), 4.60-5.00 (1H, m, CH.CH2), 5.31 and 5.54 (each 1H, d, J 14, CH2Ar), 5.95 (1H, d, J 13.5, S.CH=CH), 6.12 (dq, J 7 and 0.5 Hz, CH3CH for Z-isomer), 6.38 (dq, J 7 and 1 Hz, CH3CH for E-isomer), 7.15 (1H, dd, J 13.5 and 10.5 Hz; NH.CH=CH), 7.77 and 8.22 (each 2H, d, J 9 Hz, aromatic protons).
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[C:7]1([CH:13]([CH3:16])[C:14]#[N:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.ClCCl>[C:7]1([CH:13]([CH3:16])[C:14](=[NH:2])[NH2:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C#N)c1ccccc1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C(=N)N)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Ammonium chloride (535 mg, 10.0 mmol) was suspended in toluene (3 ml), cooled to 0° C., under nitrogen then trimethylaluminium (5 ml, 2M in toluene) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 2 h. Then 2-phenylpropionitrile (1.33 ml, 10.0 mmol) in toluene (2 ml) was added and heated to 80° C. for 17 h. The reaction mixture was poured onto a slurry of silica (20 g) in dichloromethane (20 ml) and stirred for 5 min. It was filtered and the filtrate concentrated in vacuo. Trituration of the residue with diethyl ether afforded the title compound as a solid in 95% yield, 1.75 g.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=1.CSC.[CH:22]1([Mg]Br)[CH2:24][CH2:23]1>O1CCCC1.[Cu](I)I>[C:5]1([O:4][C:2]([N:14]2[CH:15]=[C:16]([F:18])[CH:17]([CH:22]3[CH2:24][CH2:23]3)[C:12]([Br:11])=[C:13]2[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Fc1cncc(Br)c1
Reactant: Br[Mg]C1CC1
Agent: I[Cu]I
Solvent: CSC
Solvent: C1CCOC1
Product: O=C(Oc1ccccc1)N1C=C(F)C(C2CC2)C(Br)=C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Phenyl chloroformate (4.2 mL, 0.033 mol) was added to a mixture of 3-bromo-5-fluoro-pyridine (5.5 g, 0.031 mol), dimethyl sulphide (15.32 mL, 0.209 mol) and copper iodide (5.95 g, 0.031 mol) in anhydrous tetrahydrofuran (50 mL) at RT and the reaction mixture was stirred for 40-50 min. To this suspension, cyclopropylmagnesiumbromide (66.75 mL, 0.033 mol, 0.5 M solution in tetrahydrofuran) was added at −25 to −20° C. over a 30-40 min period. The mixture was stirred at this temperature for 30 min, and then warmed slowly to RT over 1.0-1.5 hrs. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (200 mL), followed by extraction of the aqueous layer with ethyl acetate (3×200 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (2×100 mL), and dried over anhydrous sodium sulphate to afford the crude compound, which was purified by silica gel chromatography using 0-5% ethyl acetate-hexane gradient. This yielded crude phenyl 3-bromo-4-cyclopropyl-5-fluoro-4H-pyridine-1-carboxylic acid phenyl ester.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[NH2:7][C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])=[O:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>>[F:31][C:28]([F:29])([F:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]([N:17]1[CH2:16][CH2:15][N:14]([C:11]2[N:12]=[N:13][C:8]([NH:7][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:6])=[CH:9][CH:10]=2)[CH2:19][CH2:18]1)=[O:21]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C(O)C1CC1
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)C1CC1

Procedure:
Following the procedure of Example 2, making variations only as required to use cyclopropanecarboxylic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (32% yield). 1H NMR (300 MHz, CDCl3) δ 10.07, 8.40, 7.72, 7.61, 7.53, 7.34, 7.03, 4.02-3.82, 3.67-3.55, 3.49-3.46, 3.30-3.27, 2.09-2.01, 1.09-1.04, 0.88-0.82. MS (ES+) m/z 420.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36]([O:42][CH2:43][Cl:44])(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>CC(C)=O>[Cl-:44].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH2:43][O:42][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[N:31]1
Reactant: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CC(C)=O
Product: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(C[NH+]1CN(COC(=O)C(C)(C)C)C=N1)c1ccc(F)cc1F
Product: [Cl-]
Reaction time: 88 h

Procedure:
To a mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone (0.48 g) and acetone (10 ml) was added chloromethyl pivalate (2.9 ml), and the mixture was stirred under reflux. After 88 hours, chloromethyl pivalate (1.45 ml) was added to the mixture. The mixture was further stirred for 14 hours under reflux. The reaction mixture was concentrated under reduced pressure. To the residue was added diethyl ether (8 ml), and the resulting powder was collected by filtration. The powder was subjected to ODS column chromatography (eluent: methanol/water=3/2) to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(2,2-dimethylpropanoyloxy)methyl]-1H-1,2,4-triazolium chloride (Compound 2, 0.25 g) as a white powder.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[C:15]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)[CH3:18])[CH:14]=[C:13]([CH:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=3)[CH3:28])[CH:12]=2)[CH3:10])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.N#N>O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[C:15]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH3:18])[CH:14]=[C:13]([CH:27]([C:29]3[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=3)[CH3:28])[CH:12]=2)[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)c2cc(C(C)c3ccc(OC)cc3)cc(C(C)c3ccc(OC)cc3)c2)cc1
Agent: Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: O
Product: CC(c1ccc(O)cc1)c1cc(C(C)c2ccc(O)cc2)cc(C(C)c2ccc(O)cc2)c1
Temperature: 180 °C

Procedure:
A 250 mL round-bottomed flask equipped with magnetic stirring bar was charged with racemic 1,3,5-tris(1-(4-methoxyphenyl)ethyl)benzene (5) (19.6 g, 41 mmol) and pyridine hydrochloride (56.8 g, 0.49 mol, 12 equiv). The mixture was protected with an N2 bubbler and heated in a 180° C. oil bath for 5 h. The mixture was allowed to cool briefly to ˜120° C. and then 55° C. H2O (100 mL) was added slowly to the mixture with vigorous stirring. The mixture was extracted three times with EtOAc (100 mL portions). The collected organic phase was washed with brine (200 mL) and dried over anhydrous MgSO4. Rotary evaporation gave a thick, colorless oil that foamed under vacuum. Yield: 17.17 g (95%). 1H NMR (300 MHz, DMSO-d6, δ, ppm): 9.12 (s, 3OH), 6.98 (d, J=8.6 Hz, 6H), 6.90 (s, 3H), 6.63 (d, J=8.6 Hz, 6H), 3.92 (q, J=7.2 Hz, 3H), 1.44 (d, J=7.5 Hz, 9H). 13C NMR (75 MHz, DMSO-d6, δ, ppm): 155.35, 146.59, 146.53, 146.48, 136.69, 136.67, 136.65, 128.04, 123.88, 123.65, 114.96, 43.49, 43.46, 22.09, 22.04. Anal. calcd for C30H30O3.0.65H2O: C, 80.02; H, 7.01. Found: C, 80.38; H, 7.41.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.C(OCC)(=O)C.O.[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[O:4]([C:5]1[N:6]=[C:7]([C:22]#[N:23])[CH:8]=[CH:9][CH:10]=1)[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:2]=1
Reactant: Brc1ccccc1Oc1ccccn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(Oc2ccccc2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Next, to a solution of the resulting 2-bromo-phenoxy-pyridine (1.0 g, 4.0 mmol) in N,N-dimethylformamide (30 mL) were added zinc cyanide (940 mg, 8.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (924 mg, 0.8 mmol) under nitrogen atmosphere, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and 6-phenoxy-pyridine-2-carbonitrile (524 mg, 67%) was obtained as a white solid.