Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH3:13][N:14]1[CH2:18][CH2:17][CH:16]([SH:19])[CH2:15]1>CN(C)C=O>[CH3:13][N:14]1[CH2:18][CH2:17][CH:16]([S:19][C:4]2[C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=[CH:11][N:12]=2)[CH2:15]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: CN1CCC(S)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Sc2ncccc2C(=O)O)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 80 g (2 mole) of 60% sodium hydride (in mineral oil) in 800 ml of dry dimethylformamide, all heated to 60° C. and using nitrogen gas flow was added dropwise, a solution of 157.0 g (1 mole) of 2-chloronicotinic acid and 117 g (1 mole) of 1-methyl-3-pyrrolidinethiol in 300 ml of dimethylformamide at a rate which maintained a temperature of 60°-67° C. The mixture was heated to 65° C. for 6 hr and allowed to stand overnight at room temperature and then filtered. The collected solid was suspended in one liter of isopropyl alcohol and hydrogen chloride was bubbled into the suspension until a pH of 6.2 was reached. The mixture was brought to a boil and filtered. The solid was dissolved in 2 liters of water and extracted with isopropyl ether. The pH was adjusted to 6.0 and the solution was concentrated to a volume of 800 ml and placed in a refrigerator. The resulting solid (85 g) collected by filtration, was a mixture consisting of about 85% of the title compound and 15% sodium chloride. A sample portion of this was crystallized once from ethanol and twice from isopropyl alcohol-water. The recrystallized product decomposed at about 225° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)[CH3:29].C(C([Sn])=C(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([CH:28]=[CH2:29])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC([Sn])=C(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1cncc2cccc(S(=O)(=O)N3CC[C@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Yield: 21298.1 %

Procedure:
A solution of Intermediate 1a (250 mg) obtained in Example 1-1, Step A, 2,6-di(tert-butyl)-4-methylphenol (0.5 mg, Tokyo Kasei Kogyo), and tri(n-butyl)vinyltin (0.25 ml, Tokyo Kasei Kogyo) in toluene (8 ml) was added with tetrakis(triphenylphosphine)palladium(0) (13 mg, Kanto Chemicals) under a nitrogen gas atmosphere, and the mixture was refluxed by heating for 12 hours. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (195 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[Li+].[OH-]>CO.O>[C:15]([N:9]1[C:10]([C:11]([F:13])([F:14])[F:12])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)n1ncc(C(=O)O)c1C(F)(F)F
Yield: 80.3 %

Procedure:
To a solution of 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (5 g, 21.2 mmol, purchased from Bionet) in CH3OH (45 mL) and water (45 mL) was added LiOH (0.54 g, 22.5 mmol). The reaction mixture was stirred at reflux for 4 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH 2 with concentrated HCl. The resulting mixture was then extracted with ethyl acetate three times. The combined organic extracts were concentrated in vacuo to give 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4.02 g, 80%), which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10](Cl)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH3:13][O:14][C:15]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:16]=1[CH2:17][N:18]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[CH:24]=[CH:23][C:22]=2[N:21]=[C:20]([NH:32][NH2:33])[C:19]1=[O:34].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]([NH:33][NH:32][C:20]1[C:19](=[O:34])[N:18]([CH2:17][C:16]2[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:15]=2[O:14][CH3:13])[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[CH:24]=[CH:23][C:22]=2[N:21]=1)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: COc1ccc(Cn2c(=O)c(NN)nc3ccc4ccccc4c32)c(OC)c1
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)NNc1nc2ccc3ccccc3c2n(Cc2ccc(OC)cc2OC)c1=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.2 %

Procedure:
A solution of (diethoxyphosphoryl)acetyl chloride (480 mg, 2.2 mmol) in dry tetrahydrofuran (10 ml) was added to a mixture of 1-(2,4-dimethoxybenzyl)-3-hydrazinobenzo[f]quinoxalin-2(1H)-one (750 mg, 2 mmol) and dry triethylamine (220 mg, 2.2 mmol) in dry tetrahydrofuran (40 ml). The mixture was stirred at room temperature for 1.5 h and filtered. The filtrate was evaporated to give 1.1 g of the title compound as a crude product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:48])([F:47])[C:9]1[CH:10]=[C:11]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:12][N:13]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([C:37]([OH:39])=O)[CH:30]=1)[C:14]([O:16][CH3:17])=[O:15].[C:49](=[N:52]O)([NH2:51])[CH3:50]>CN(C)C=O.C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]1[CH:40]=[C:11]([CH:10]=[C:9]([C:8]([F:7])([F:48])[F:47])[CH:42]=1)[CH2:12][N:13]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:30]=[C:31]([C:37]2[O:39][N:52]=[C:49]([CH3:50])[N:51]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:14](=[O:15])[O:16][CH3:17]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(=O)O)ccc1OC
Reactant: CC(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(-c2nc(C)no2)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.14 mL, 0.28 mmol) and a few drops of dimethylformamide were added to a solution of the title compound from Example 145 (86 mg, 0.14 mmol) in methylene chloride. The reaction mixture was stirred at room temperature for 1 h then concentrated in vacuo. The crude product was re-dissolved in anhydrous dichloroethane, and acetamide oxime (16 mg, 0.21 mmol) was added along with a few drops of dimethylformamide to increase solubility. The reaction was heated to and maintained at reflux overnight. Once the reaction cooled to room temperature, the solvent was removed through evaporation. The oil was taken up in methylene chloride, washed with water, then brine, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by preparative thin layer chromatography using 50% EtOAc/hexane. 1H NMR (CDCl3, 600 MHz) δ 8.15 (s, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.43-7.56 (m, 3H), 7.35 (d, J=7.8 Hz, 1H), 7.07 (m, 1H), 4.20-4.60 (m, 4H), 3.81 (s, 3H), 3.70 (m, 3H), 2.46 (s, 3H). LC-MS (M+1) 647.9 (4.40 min).
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH2:2].[CH2:16]([O:18][CH2:19][CH2:20][O:21]CCO)[CH3:17]>[O-]CC.[Na+].C(O)C>[CH:1]([CH:3]1[CH2:5][C:4]1([C:11]([O:13][CH2:14][CH2:15][O:21][CH2:20][CH2:19][O:18][CH2:16][CH3:17])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH2:2]
Reactant: CCOCCOCCO
Reactant: C=CC1CC1(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CC1CC1(C(=O)OCC)C(=O)OCCOCCOCC

Procedure:
Employing a procedure similar to that of Example IV diethyl 2-vinylcyclopropane-1,1-dicarboxylate was reacted with a polyalkoxylated alcohol in the presence of sodium ethoxide catalyst. For the process 33.77 g (0.159 mol) diethyl 2-vinylcyclopropane-1,1-dicarboxylate and 7.12 g (0.053 mol) 2-(2-ethoxyethoxy)ethanol were heated at reflux until the theoretical amount of ethanol was recovered. After removal of unreacted diethyl 2-vinylcyclopropane-1,1-dicarboxylate (19.63 g), 8.4 g crude ethyl 2-(2-ethoxyethoxy)ethyl 2-vinylcyclopropane-1,1-dicarboxylate was obtained. Redistillation of the crude product provided 4.9 g high purity 2-(2-ethoxyethoxy)ethyl 2-vinylcyclopropane-1,1-dicarboxylate. B.p. 110°-112° C. at 0.01 mm Hg; nD24.5 1.4608. Infrared and nuclear magnetic resonance spectra were consistent with the desired structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[C:22]([Cl:24])[C:21]([N+:25]([O-])=O)=[CH:20][C:19]=4[F:28])=[C:11]3[C:10]([I:29])=[N:9]2)=[CH:5][CH:4]=1.CCO>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[C:19]([F:28])=[CH:20][C:21]([NH2:25])=[C:22]([Cl:24])[CH:23]=4)=[C:11]3[C:10]([I:29])=[N:9]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c([N+](=O)[O-])cc4F)ccnc32)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c(N)cc4F)ccnc32)cc1
Temperature: 70 °C
Yield: 74.9 %

Procedure:
A mixture of 1-(4-methoxybenzyl)-4-(5-chloro-2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrazolo[3,4-b]pyridine (2.85 g, 5.14 mmol), SnCl2 dihydrate (4.64 g, 20.6 mmol) and EtOH (70 mL) was heated to 70° C. for 8 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with saturated aqueous Na2CO3, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (2.02 g, 64% yield) as a light yellow solid. LRMS (APCI pos) m/e 524.9 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[O:18][CH2:17][CH2:16][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[F:15])[N:7]=1.[IH:19].[Na+].[I-]>O>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:6]2[N:7]=[C:2]([I:19])[C:3]3[O:18][CH2:17][CH2:16][C:4]=3[N:5]=2)[CH:13]=1
Reactant: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)CCO2
Reactant: I
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc(Cl)cc1-c1nc(I)c2c(n1)CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]-pyrimidine (80 mg, 0.28 mmol, 1 eq) in a 57% HI solution in water (2 ml) at rt. was added NaI (206 mg, 1.41 mmol, 5 eq). The reaction mixture was stirred at r.t. overnight and then poured onto ice. The product was extracted with chloroform and the aqueous layer was neutralized with NaHCO3 and extracted further with more chloroform. The organic layers were combined washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude residue 2-(5-chloro-2-fluorophenyl)-4-iodo-6,7-dihydrofuro[3,2-d]pyrimidine that was not further purified.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][NH:15][C@H:14]([C:17]([NH:19][C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[O:18])[CH2:13]1)(=[O:11])=[O:10].Cl.[CH3:26][C:27]1([CH3:39])[CH2:32][CH2:31][CH2:30][N:29]([C:33]2([C:36](O)=[O:37])[CH2:35][CH2:34]2)[CH2:28]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:36]([C:33]2([N:29]3[CH2:30][CH2:31][CH2:32][C:27]([CH3:39])([CH3:26])[CH2:28]3)[CH2:35][CH2:34]2)=[O:37])[C@H:14]([C:17]([NH:19][C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[O:18])[CH2:13]1)(=[O:11])=[O:10]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)CN2)CC1
Reactant: CC1(C)CCCN(C2(C(=O)O)CC2)C1
Agent: Cl
Product: CC1(C)CCCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)C1
Yield: 15 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7A with 1-(3,3-dimethylpiperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16M carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(3,3-dimethylpiperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as a light yellow solid (15%). MS ISP (m/e): 533.3 (100) [(M+H)]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=1[F:26])=[O:18].[CH3:27][C:28]1([CH3:45])[O:32][CH:31]([CH2:33]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:30][O:29]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([O:25][CH2:33][CH:31]2[CH2:30][O:29][C:28]([CH3:45])([CH3:27])[O:32]2)[CH:22]=[CH:21][C:20]=1[F:26])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reactant: O=C(c1cc(O)ccc1F)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OCC(COc2ccc(F)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)O1
Temperature: 110 °C
Reaction time: 0.83 h

Procedure:
Compound 512 (54 mg, 0.14 mmol) was dissolved in acetonitrile (4 mL) in a reaction vial. Compound 506 (61 mg, 0.21 mmol) and K2CO3 (30 mg, 0.21 mmol) were added. The reaction vial was flushed with argon, closed and then stirred at 110° C. for 50 min. in a microwave oven, followed by reflux in a oil bath for 24 h. The reaction mixture was concentrated in vacuo and purified by continuously gradient flash chromatography using EtOAc/petroleum ether (40-60)(v:v=1:7 to 1:3) as the eluent, affording the title compound as a yellow oil. 13C NMR (CDCl3) δ 190.6, 159.1 (dd), 154.7, 154.5 (d), 154.4 (dd), 147.8, 134.7, 132.9, 129.6, 127.9 (d), 124.4 (dd), 124.2 (dd), 120.6 (d), 117.1 (d), 116.0, 115.1 (d), 112.9, 111.6 (dd), 109.9, 104.9 (dd), 73.9, 69.6, 66.6, 26.8, 25.4
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Br[C:18]1[O:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[O:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)o1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C#CC=C2CCN(c3ccc([N+](=O)[O-])o3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of the Compound of Example 3 (100 mg, 0.47 mmol), 2-bromo-5-nitrofuran (98 mg, 0.51 mmol) and potassium carbonate (72 mg, 0.52 mmol) in DMF (2 mL) was stirred at r.t. for 4 h. Afterwards, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography eluting with Petroleum Ether-EtOAc 6:4 affording the title product (94 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([I:13])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH2:14](O)[CH2:15][CH2:16][OH:17].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[O:17][CH2:16][CH2:15][CH2:14][O:7]2)[CH:8]=[C:9]([I:13])[C:10]=1[O:11][CH3:12]
Reactant: OCCCO
Reactant: COc1cc(C=O)cc(I)c1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(C2OCCCO2)cc(I)c1OC

Procedure:
3,4-dimethoxy-5-iodobenzaldehyde (41) (FIG. 22) (5.814 g,19.9 mmole), 1,3-propanediol (6.13 g, 79.6 mmole), pyridinium para-toluenesulfonate (2.0 g, 7.96 mmole) and 100 ml dry benzene were refluxed with Dean-Stark removal of the benzene-water azeotrope overnight. The benzene was removed in vacuo and the remaining oil redissolved in diethyl ether and was washed with 10% NaHCO3 and H2O. The organic layer was washed over MgSO4, and concentrated to a white solid in vacuo. (6.823 g, 98%). The solid can be recrystallized from hexane/ethyl acetate.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]([CH2:32][O:33]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[C:1]1([CH2:7][O:8][CH:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:14][CH:13]=2)[CH2:32][OH:33])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1ccc(OCC(CO)OCc2ccccc2)cc1

Procedure:
An about 14.6 g portion of 1-[2-(phenylmethoxy)-3-(triphenylmethoxy)propoxy]-4-tetradecylbenzene was dissolved in about 50 ml of tetrahydrofuran. To this solution was added about 50 ml of methanol and about 100 mg of p-toluenesulfonic acid. The mixture was stirred under argon for several hours and the solvents were then removed. The residue was dissolved in ether, washed with aqueous sodium bicarbonate, dried and the ether evaporated. The residue was purified by chromatography on silica gel, eluting with hexane:ether (about 12:1), giving about 7.6 g of the desired title compound, mp 50°-51° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.B(F)(F)F.CCOCC.C(OCC)(=O)C>CCOCC.B(F)(F)F.CCOCC>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[CH:10][N:9]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: C1=COCCC1
Reactant: Fc1ccc(-c2nc[nH]c2-c2ccc(F)cc2)cc1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Fc1ccc(-c2ncn(C3CCCCO3)c2-c2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A mixture of 124 g (0.484 mole) of 4,5-bis(4-fluorophenyl)imidazole, 84 g (1.0 mole) dihydropyran, 20 g boron trifluoride etherate and 1 l ethyl acetate was heated at reflux over a weekend. Analysis by TLC (ethyl acetate) showed the presence of some unchanged starting material, so 20 g (~0.24 mole) of dihydropyran and 5 g boron trifluoride etherate was added and heating was continued overnight. The mixture was then diluted with 1 l ether and washed with 10% sodium bicarbonate solution (3×1 l). The organic layer was dried and concentrated on a rotary evaporator. The residual solid was recrystallized from methylcyclohexane (removing some insoluble starting material by filtration) to give 140.2 g (85%) of 4,5-bis(4-fluorophenyl)-1-(2-tetrahydropyranyl)imidazole as a white solid, mp 149°-152°. F-NMR indicated purity ~95%. A smaller run was chromatographed to give pure material mp 158°-9°. IR: 3.25μ (=CH); 3.38, 3.49μ (sat. CH); 6.22, 6.28, 6.41, 6.60, 6.69μ (C=C and/or C=N); 8.20μ (CF); 9μ region (C--O--C). H-NMR: m(1.4-2.1 δ, 6H); m (3.4 δ, 1H); m (4.0 δ, 1H); m (4.7 δ, 1H); m (6.6-7.5 δ, 8H); s (7.8 δ, 1H). F-NMR: two multiplets (112.4 25 δ and 116.5 δ, each decouples to a singlet).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][NH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.[CH3:24]I>CN(C)C=O.C(OCC)(=O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[N:14]=[CH:13][N:12]([CH3:24])[C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ncn(C)c2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
1.8 g of sodium hydride (50% in white oil) is added in incremental portions to a solution of 10.5 g of 4,5-bis(4-methoxyphenyl)imidazole in 50 ml of absolute dimethylformamide. The mixture is agitated for another 30 minutes and then 5.35 g of methyl iodide in 50 ml of dimethylformamide is dropped thereto. After 60 minutes, the mixture is poured into ice water, the product taken up in ethyl acetate, the organic solution dried over sodium sulfate and concentrated under vacuum. The residue is recrystallized from benzene, thus obtaining 9.59 g of 4,5-bis(4-methoxyphenyl)-1-methylimidazole, mp 122°-123°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H].O1C2C=CC(CCC(N3CCCCC3)=O)=CC=2OC1>C(O)C.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Agent: [Pd]
Agent: O=C(CCc1ccc2c(c1)OCO2)N1CCCCC1
Solvent: CCO
Product: O=C(O)CCc1ccc2c(c1)OCO2
Yield: 82.6 %

Procedure:
3-benzo-1,3-dioxol-5-ylacrylic acid (2 g) was hydrogenated in ethanol (50 ml) over 5% Pd-C under a pressure of hydrogen at 10 psi for 40 mins to give 3-benzo-1,3-dioxol-5-ylpropionic acid (1.67 g, 80% yield) as a solid, m.p. 86.1°-88.3° C. (Lit m.p. 87-88° C.)10 7.2 Synthesis of 3-benzo-1,3-dioxol-5-ylpropionic acid piperidide (RV-C03)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].BrCCCCCC(O[C:17]([CH3:20])([CH3:19])[CH3:18])=O>C=C(C)C>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:6]
Reactant: CC(C)(C)OC(=O)CCCCCBr
Reactant: O=C(O)CCCBr
Agent: C=C(C)C
Product: CC(C)(C)OC(=O)CCCBr
Yield: 54 %

Procedure:
4-Bromobutanoic acid (8 g, 47.9 mmol) and iso-butene (60 ml) were reacted by the same procedure as described in Example 1 for the preparation of tert-butyl 6-bromohexanoate to give the title material (5.7 g, 54%) as a colorless liquid (b.p. 62-64° C./10 mmHg).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:7]=1[C:8](O)=[O:9])([CH3:4])[CH3:3].N1C=CC=CC=1.C(Cl)(=O)C([Cl:25])=O>C(#N)C>[CH3:1][C:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:7]=1[C:8]([Cl:25])=[O:9])([CH3:4])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)Oc1cccc(Cl)c1C(=O)O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)Oc1cccc(Cl)c1C(=O)Cl
Reaction time: 0.5 h

Procedure:
2-[(1,1-dimethylethyl)oxy]-6-chlorobenzoic acid (68.6 mg, 0.3 mmol) was weighed into a 1 dram septum-capped vial containing a micro stir bar under nitrogen. Dry acetonitrile (300 microliter), dry pyridine (24 microliter, 0.3 mmol) and oxalyl chloride (26 microliter, 0.3 mmol) were added in order to the vial using microliter syringes. The yellow homogeneous solution was stirred for 30 minutes to afford a solution of 2-[(1,1-dimethylethyl)oxy]-6-chlorobenzoyl chloride.