Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:28][C:29](=[O:31])[CH3:30])([CH2:23][O:24][C:25](=[O:27])[CH3:26])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](B2OCC(C)(C)CO2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2].C([O:39][C:40]1[CH:45]=[CH:44][C:43](Br)=[C:42]([F:47])[CH:41]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+].O>COCCOC>[C:25]([O:24][CH2:23][C:6]([NH:28][C:29](=[O:31])[CH3:30])([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:43]2[CH:44]=[CH:45][C:40]([OH:39])=[CH:41][C:42]=2[F:47])=[CH:13][CH:14]=1)(=[O:27])[CH3:26]
Reactant: Fc1cc(OCc2ccccc2)ccc1Br
Reactant: CC(=O)NC(CCc1ccc(B2OCC(C)(C)CO2)cc1)(COC(C)=O)COC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)NC(CCc1ccc(-c2ccc(O)cc2F)cc1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
A mixed solution of N-[1,1-bis(acetoxymethyl)-3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]propyl]acetamide (867 mg) of Reference Example 9, 1-benzyloxy-4-bromo-3-fluorobenzene (674 mg), sodium hydrogen carbonate (1.01 g) and tetrakistriphenylphosphine palladium (46 mg) in 1,2-dimethoxyethane (15 mL)-water (5 mL) was stirred at 65° C. for 5 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To a solution of the residue in methanol (30 mL) were added palladium carbon (10%, 0.3 g) and ammonium formate (517 mg), and the mixture was stirred at room temperature for 6 hr under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.56 g) as white amorphous crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][C:43]1[C:48]([CH2:49]O)=[CH:47][CH:46]=[CH:45][N:44]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:49][C:48]2[C:43]([CH3:42])=[N:44][CH:45]=[CH:46][CH:47]=2)=[CH:4][C:3]=1[C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1)=[O:10]
Reactant: Cc1ncccc1CO
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(O)ccc2Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNC(=O)c2cc(OCc3cccnc3C)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methyl 4-({[(2-chloro-5-hydroxyphenyl)carbonyl]amino}methyl)benzoate (100 mg, 0.31 mmol) in THF (5 ml) was treated with triphenylphosphine (1.2 eq, 98 mg, 0.37 mmol), (2-methyl-3-pyridinyl)methanol (38 mg, 0.31 mmol) and diisopropylazodicarboxylate (1.2 eq, 110 ul, 0.56 mmol) and stirred at room temperature for 4 hours. Mixture diluted with methanol and purified by SCX cartridge eluting with methanol first then 2M ammonia in methanol. Basic fractions combined and evaporated to give the title compound as an off-white solid. MS (ES+) m/z 425 [M+H]+ (C23H2135ClN2O4). 1H-NMR (400 MHz, d6-DMSO) δ 3.85 (3H, s), 4.51 (2H, d, J 6), 5.18 (2H, s), 7.10-7.96 (9H, m), 8.42 (1H, dd, J 1.6, J 4.8), 9.07 (1H, t, J 6).
Reaction SMILES: [N+:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([O-])=O.[N:11]([O-:13])=[O:12].[Na+].[Cl:15][CH:16](C(=O)C)[C:17](=[O:19])[CH3:18]>>[Cl:15][C:16](=[N:1][NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:17](=[O:19])[CH3:18]
Reactant: O=N[O-]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: O=[N+]([O-])Nc1ccccc1
Agent: [Na+]
Product: CC(=O)C(Cl)=NNc1cccc([N+](=O)[O-])c1

Procedure:
3-nitroaminobenzene is reacted with sodium nitrite and 3-chloro-2,4-pentanedione as in Example 1 to yield 1-chloro-1-[(3-nitrophenyl)hydrazono]-2-propanone.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[Cl:15][S:16]([C:10]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7])(=[O:18])=[O:17]
Reactant: O=C(O)c1ccccc1OC(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1OC(F)(F)F
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A solution of 2-trifluoromethoxy benzoic acid [1979-29-9](1.0 g) was added in small batches to chlorosulfonic acid (3.2 mL) at 0° C. After completion of the addition, the reaction mixture was stirred at 70° C. for 4 hours then left at room temperature overnight and heated at 75° C. for another 3 hours. After such time the reaction was slowly poured onto ice, and the precipitate was then filtered, washed with water and dried to yield the title compound as a white solid (1.2 g). MS (m/e): 303.3 (M-H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:15]([O:12][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(Br)cc1C(=O)O

Procedure:
The reaction of methyl 5-bromo-2-hydroxyl-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-Allyloxy-5-bromo-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.98 (s, —CO2H); 7.73 (m, larom. H); 7.62 (m, 1 arom. H); 7.07 (m, 1 arom. H); 5.99 (m, —CH═CH2); 5.47, 5.25 (2 d-like, CH═CH2); 4.62 (d-like, CH2—CH═CH2). 13C-NMR (100 MHz, d6-DMSO): 165.99 (C═O); 156.10; 135.10; 133.00; 132.65; 123.86; 117.15; 116.12; 111.34; 68.84.
Reaction SMILES: [Cl:1][CH2:2][Si:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])[CH3:4].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C(C)=CC=CC=1>[ClH:1].[CH2:6]([Si:3]([CH2:2][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:5])[CH3:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[Si](C)(CCl)Cc1ccccc1
Reactant: C1CCNC1
Solvent: Cc1ccccc1C
Product: C[Si](C)(Cc1ccccc1)CN1CCCC1
Product: Cl

Procedure:
9.9 g of chloromethyl-benzyl-dimethylsilane and 8.9 g of pyrrolidine are refluxed in 40 ml of xylene for 6 hours, then the reaction mixture is washed 5 times with a total of 250 ml of water at room temperature. The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to solvent-free. The slightly yellow oily residue is dissolved in 20 ml of ethyl acetate and the solution is acidified to pH 4.5 by adding ethanolic hydrogen chloride solution. After drying the precipitate the named product is obtained in a yield of 11.3 g (94%), m.p.: 140°-140.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[I-:11].[Na+].[CH3:13]C(=O)CC>>[CH3:13][O:10][C:8](=[O:9])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([I:11])[CH:7]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: [I-]
Reactant: CCC(C)=O
Agent: [Na+]
Product: COC(=O)c1ccnc(I)c1
Yield: 92.4 %

Procedure:
A solution of 2-chloro-pyridine-4-carboxylic acid (5 g, 31.7 mmol) in butan-2-one (150 ml) was heated under reflux with sodium iodide for 6 h to afford the 2-iodo-isonicotinic acid (7.3 g, 92.4% yield) following extractive aqueous workup. This material was dissolved in THF (50 ml) and esterified with fresh etheral diazomethane solution (44 ml, 0.55 mol/l). After evaporation of the solvent and filtration through a pad of silica gel, [elution with CH2Cl2/(2M NH3 MeOH)=19:1] the title compound (2.3 g, 44%) was obtained as a dark yellow oil. MS: m/e=263.0 (M+).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].O[CH:9]1CC[CH:15]2[CH:10]1[CH2:11][CH:12]=[C:13]([O:18][CH3:19])[CH2:14]2>N1C=CC=CC=1>[C:5]([O:4][CH:1]1[CH2:9][CH2:10][CH:15]2[CH:2]1[CH2:11][CH:12]=[C:13]([O:18][CH3:19])[CH2:14]2)(=[O:7])[CH3:6]
Reactant: COC1=CCC2C(O)CCC2C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC1=CCC2C(CCC2OC(C)=O)C1
Reaction time: 60 h
Yield: 91.7 %

Procedure:
Acetic anhydride (62.3 g) was added to a solution of 7-hydroxy-3-methoxybicyclo[4,3,0]non-3-ene (51.4 g; prepared as described in Reference Example 2) in pyridine (166 ml), and the mixture was left to stand at the ambient temperature for 60 hours. Concentration under reduced pressure gave 7-acetoxy-3-methoxybicyclo[4,3,0]non-3-ene (58.9 g).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[C:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)(=[O:10])[CH3:9]>CN(C=O)C.CS(C)=O>[CH3:9][C:8]1([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:2][O:10]1
Reactant: CC(=O)c1ccncc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC1(c2ccncc2)CO1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Trimethylsulfonium iodide (43.8 g, 210 mmol) was dissolved in 100 mL DMF and NaH (19.8 g, 495 mmol) was added. The reaction mixture was stirred for 5 min. and a solution of 4-acetylpyridine (20 g, 165 mmol) in 20 mL DMSO was added dropwise at RT. After the addition was complete, reaction mixture was stirred at RT for 2 h after which it was poured into ice water. The product was extracted with EtOAc, organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. Yield: 21 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:48]=[C:47]([O:49][C:50]2[CH:69]=[CH:68][C:53]3[N:54]([CH3:67])[C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([CH:64]([CH3:66])[CH3:65])[CH:59]=4)=[N:56][C:52]=3[CH:51]=2)[CH:46]=[CH:45][N:44]=1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH:64]([C:60]1[CH:59]=[C:58]([NH:57][C:55]2[N:54]([CH3:67])[C:53]3[CH:68]=[CH:69][C:50]([O:49][C:47]4[CH:46]=[CH:45][N:44]=[C:43]([NH:42][C:15]([CH2:14][CH:11]5[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]5)=[O:17])[CH:48]=4)=[CH:51][C:52]=3[N:56]=2)[CH:63]=[CH:62][CH:61]=1)([CH3:66])[CH3:65]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: CC(C)c1cccc(Nc2nc3cc(Oc4ccnc(N)c4)ccc3n2C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)c1cccc(Nc2nc3cc(Oc4ccnc(NC(=O)CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3n2C)c1
Temperature: 25 °C

Procedure:
To a mixture of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (1 eq) in N,N-dimethyl formamide and N,N,disopropylethylamine (4 eq) was added HATU (2 eq) and the mixture was stirred at ambient temperature until it becomes homogeneous. To it was added 5-(2-aminopyridin-4-yloxy)-N-(3-isopropylphenyl)-1-methyl-1H-benzo[d]imidazol-2-amine (1 eq) and 4-(dimethylamino)pyridine (0.05 eq) and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and the resulting tert-butyl 4-((4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-ylcarbamoyl)methyl)piperidine-1-carboxylate was purified by HPLC. HPLC=4.63 min; MS: MH+=599.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][C:23](=[O:25])[CH3:24].O>O1CCCC1>[C:23]([CH:22]([C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[Cl:14])[C:10](=[S:11])[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])(=[O:25])[CH3:24]
Reactant: CC(=O)Cc1ccc(Cl)cc1Cl
Reactant: Fc1ccc(N=C=S)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C(C(=S)Nc1ccc(F)cc1F)c1ccc(Cl)cc1Cl
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
2,4-Difluorophenyl isothiocyanate (0.27 mL, 2.0 mmol) was added to a stirred suspension of sodium hydride (60% in mineral oil) (112 mg, 2.8 mmol) in anhydrous tetrahydrofuran (4 mL) cooled in an ice-water bath under a nitrogen atmosphere. A solution of (2,4-dichlorophenyl)-2-propanone (570 mg, 2.8 mmol) in tetrahydrofuran (4 mL) was added dropwise over 5 min. The resultant yellow solution was stirred at 5-10° C. for 1 h. Water (10 mL) was carefully added, and the reaction mixture was extracted with ethyl acetate (10 mL). The aqueous phase was acidified to pH 3 with 1 N aqueous HCl, then extracted with ethyl acetate (20 mL). The organic extract was washed with water (10 mL) and brine (10 mL), dried over MgSO4, and concentrated to leave a solid. The solid was triturated with hexanes/ethyl acetate (2:1), collected on a glass frit, and air-dried to give the title compound as a white solid (240 mg). MS: 373 amu (AP+).
Reaction SMILES: [Cu:1]=O.[CH2:3]([N+:15]([O-:18])([CH3:17])[CH3:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CCOP(OC1N=C(Cl)C(Cl)=CC=1Cl)(OCC)=S>O>[NH3:15].[Cu:1].[CH2:3]([N+:15]([O-:18])([CH3:16])[CH3:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=[Cu]
Agent: CCCCCCCCCCCC[N+](C)(C)[O-]
Agent: CCOP(=S)(OCC)Oc1nc(Cl)c(Cl)cc1Cl
Solvent: O
Product: N
Product: [Cu]

Procedure:
4.8 g technical (not purified) chlorpyrifos solid was dissolved in 160 grams of Barlox® 12 (48 g of dodecyldimethylamine oxide). This solution was mixed with 480 g of ammoniated copper carbonate concentrate prepared as in Example 1 (solution (1)) to yield a concentrated solution. The concentrated solution was diluted with 7360 grams of deionized water and the resulting solution containing 0.6% copper oxide, 0.6% dodecyldimethylamine oxide, and 0.06% chlorpyrifos was used to treat wood in a pressure cylinder.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3](=[O:14])[NH:4][N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:7]=1[Br:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(-c2ccccc2)n[nH]c1=O
Solvent: CC#N
Product: Nc1c(Br)c(-c2ccccc2)n[nH]c1=O
Reaction time: 18 h

Procedure:
4-Amino-6-phenyl-3(2H)-pyridazinone (prepared by the method of Example 1a), or according to McKillop et al., Heterocycles, 1989, 29(6), 1077) (4.69 g, 25 mmol) and N-bromosuccinimide (4.50 g, 25.3 mmol), suspended in dry acetonitrile (135 ml), was heated at reflux under a nitrogen atmosphere for 6 hours, then allowed to stand at room temperature for 18 hours. The solid was collected by filtration, washed with ethyl acetate (40 ml) and diethyl ether (40 ml), and dried in vacuo at 60° C., to afford the title compound, 6.25 g (94%), as a colourless solid. 1H NMR (400 MHz, DMSO-d6) δ12.93 (1H, s), 7.43 (5H, m), 6.69 (2H, br s); m/e (ES+) 266/268 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:11]=[CH:12][N:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([O:20][CH3:21])=[CH:15]2.CN(C=O)C>CCOC(C)=O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[CH:11][CH:12]=[N:13]2)=[N:18][CH:17]=1
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: Nc1ccc(S)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cnc2c(Sc3ccc(N)cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A RBF was charged with 4-aminothiophenol (161 mg, 1.285 mmol), 8-chloro-3-methoxy-1,5-naphthyridine (250 mg, 1.285 mmol) and 5.2 mL of DMF, and the mixture was stirred at RT for 45 min. The orange, heterogeneous mixture was diluted with EtOAc and washed with 1N NaHCO3. The aqueous portion was extracted two additional times with EtOAc and the combined organics were dried with MgSO4, filtered and concentrated. The crude oil was concentrated twice from toluene to remove DMF and the resulting solids were dried under high vacuum to provide 4-(7-methoxy-1,5-naphthyridin-4-ylthio)benzenamine as a tan solid. MS m/z=284 [M+H]+. Calc'd for C15H13N3OS: 283.35.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=[O:12])[S:10][C:3]=12.[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[OH:23].C([O-])([O-])=O.[K+].[K+].O(C1C=CC=CC=1)C1C=CC=CC=1>O.CCOC(C)=O>[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O:23][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=[O:12])[S:10][C:3]=12
Reactant: O=Cc1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 170 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
A mixture of aldehyde 232 (500 mg, 2.53 mmol), 2-fluoro-4-nitrophenol (595 mg, 3.79 mmol), K2CO3 (700 mg, 5.06 mmol) and Ph2O (3.4 mL) was stirred in a sealed tube for 12 h at 170° C. The mixture was suspended in a water/EtOAc mixture, sonicated a few minutes and filtered, the solid residue was washed successively with water, EtOAc and ether, giving crude 233 (500 mg, 1.17 mmol, 46% yield) that was used in the next step without further purification. MS (m/z): (M+1) 319.0 (14%), (M+MeOH+1) 351.0 (100%).
Reaction SMILES: C(Cl)(F)C(F)(F)C(Cl)(F)F.[F:11][C:12]([F:18])([CH:15]([F:17])[F:16])[CH2:13][OH:14].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>O>[C:25]1([CH3:26])[CH:27]=[CH:28][C:22]([S:19]([O:14][CH2:13][C:12]([F:18])([F:11])[CH:15]([F:17])[F:16])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: OCC(F)(F)C(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: FC(Cl)C(F)(F)C(F)(F)Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)F)cc1

Procedure:
Until HCFC-225cb becomes available in commercial quantities, HCFC-225cb may be prepared by a standard and well-known organic systhesis technique. For example, to prepare 1,3-dichloro-1,1,2,2,3-pentafluoropropane, 2,2,3,3-tetrafluoropropanol, tosyl chloride, and water are reacted together to form 2,2,3,3-tetrafluoropropyl p-toluenesulfonate. Then, N-methylpyrrolidone, potassium fluoride, and the 2,2,3,3-tetrafluoropropyl p-toluenesulfonate are reacted together to form 1,1,2,2,3-pentafluoropropane. Then, chlorine and the 1,1,2,2,3-pentafluoropropane are reacted to form 1,1,3-trichloro-1,2,2,3,2-pentafluoropropane. Finally, isopropanol and the 1,1,3-trichloro-1,2,2,3,2-pentafluoropropane are reacted to form 1,3-dichloro-1,1,2,2,3-pentafluoropropane. A detailed synthesis is set forth below.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:15][CH:16]([C:23]1(CN)[CH2:27][CH2:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:30][N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCN(C(C)C)C(C)C>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:15][CH:16]([C:23]1([NH:31][CH3:30])[CH2:24][CH2:25][CH2:26][CH2:27]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:6]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: NCC1(C(N)c2ccccc2)CCCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-3-(trifluoromethyl)benzoic acid (0.728 g; 3.24 mmol) in DMF (20 ml) and DIPEA (2.5 ml) was added (±)-{[amino(phenyl)methyl]cyclopentyl}methylamine D29 (1.0 g; 3.60 mmol) and HATU (1.23 g; 3.24 mmol). The resulting mixture was allowed to stir at room temperature overnight and then DMF evaporated off in vacuo. Residual material was partitioned between ethyl acetate and water. The organic layer was dried (Na2SO4) and the filtrate evaporated in vacuo. The desired product was isolated by column chromatography on silica gel using 20% diethyl ether to 100% diethyl ether in n-pentane to afford the title compound as a white solid (0.908 g; 61%). 1H NMR (CDCl3) δ: 1.47-1.83 (9H, m), 2.21 (3H, s), 5.1 (1H, m), 7.23-7.43 (6H, m), 7.58 (1H, m), 7.65 (1H, m), 7.73 (1H, m); Mass Spectrum (Electrospray LC/MS), API+: Found 411 (MH+). C21H2235ClF3N2O requires 410. Ret. time 2.04 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[CH3:26][O:27][CH2:28][C:29](O)=[O:30].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][C:29](=[O:30])[CH2:28][O:27][CH3:26])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: COCC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COCC(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A solution of tert-butyl (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (206 mg, 0.57 mmol) and methoxyacetic acid (48 μl, 0.63 mmol) in DCM (5 ml) was treated with a solution of WSCDI (120 mg, 0.63 mmol), HOBt (85 mg, 0.63 mmol) and NMM (69 μl, 0.63 mmol) in DCM (10 ml) and stirred at room temperature for 18 hours. The reaction mixture was washed with sat. NaHCO3 solution followed by brine, dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was purified on a silica column eluting with Et2O to afford the title compound as a colourless oil (230 mg, 93%).
Reaction SMILES: CN(C)CCO.C([Li])CCC.[N:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=1.[Br:20]C(Br)(Br)Br.BrC1C(C)=C(C)C=CN=1>CCCCCC.C1COCC1.O>[Br:20][C:17]1[CH:16]=[C:15]([CH3:18])[C:14]([CH3:19])=[CH:13][N:12]=1
Reactant: Cc1ccncc1C
Reactant: BrC(Br)(Br)Br
Agent: CN(C)CCO
Agent: Cc1ccnc(Br)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1cnc(Br)cc1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
71.3 g (0.8 mol) 2-(dimethylamino)-ethanol are initially introduced into 500 ml n-hexane and the mixture is cooled to 0° C. 1.0 liter (1.6 mol) n-butyllithium solution (1.6 M in n-hexane) is slowly added and the mixture is stirred at 0° C. for 15 min. A solution of 17.9 g (166.7 mmol) 3,4-lutidine in 500 ml n-hexane is then added dropwise and the mixture is stirred at 0° C. for 1 h. It is subsequently cooled to −78° C. and a solution of 331.7 g (1.0 mol) tetrabromomethane in 1.0 liter THF is added. The reaction mixture is subsequently stirred at −78° C. for 1 h and is thereafter allowed to warm to RT. It is cooled again to 0° C. and 1.5 liters water are slowly added dropwise. The phases are separated and the organic phase is washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue is first pre-purified over approx. 1 kg silica gel (mobile phase: cyclohexane/ethyl acetate 9:1, then 7:3). The product-containing fractions are combined and concentrated in vacuo. The residue is then purified again over silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). The product obtained in this way contains approx. 10% of the regioisomeric 2-bromo-3,4-dimethylpyridine.
Reaction SMILES: CN1C(=O)CCC1.[CH3:8][C:9]([O-:12])(C)[CH3:10].[Na+].CC(O)C.Br[C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Br:25])[CH:24]=1>C1(C)C=CC=CC=1>[Br:25][C:23]1[CH:22]=[N:21][CH:20]=[C:19]([O:12][CH:9]([CH3:10])[CH3:8])[CH:24]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CC(C)Oc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To NMP (15 eq, 313 mmol, 30.4 ml), NaOtBu (1.5 eq, 31.3 mmol, 3.01 g) is added portion-wise. The mixture is stirred for 1 h at r.t., then 2-propanol (15 eq, 313 mmol, 24 ml) is added over a period of 15 min, followed by the addition of 3,5-dibromopyridine (Sigma-Aldrich, St. Louis, USA) (1 eq, 20.9 mmol, 5.0 g). The resulting mixture is heated at 75° C. for 2 h. After cooling down to r.t., toluene (30 ml) is added and the mixture is washed with water, dried over MgSO4, filtered, and concentrated. Purification of the crude product using column chromatography (hexane/EtOAc) yields the title compound; [M+H]+=217.