Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2C[C@H:9]2[C:11]([O:13]CC)=O)=[CH:4][CH:3]=1.[CH3:16][C@@H:17]1[C@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:20][C:19](=[O:28])[NH:18]1.CCN(CC)CC>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:11]([N:18]2[C@@H:17]([CH3:16])[C@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:20][C:19]2=[O:28])=[O:13])=[CH:6][CH:7]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-bromo-phenyl)-1-imidazol-1-yl-propenone (1.05 eq) from Step 1, (4R, 5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (1.0 eq) or (−)-isomer and Et3N (1.2 eq) in CH3CN (0.2M) was refluxed overnight. The resulting mixture was cooled to rt, filtered on a pad of silica gel and concentrated. Crystallization in hexane:Et2O afforded the title compound as a white solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:42])[CH2:9][CH2:10][CH:11]([C:38]([O:40][CH3:41])=[O:39])[NH:12][C:13](=[O:37])[CH:14]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH:15][C:16](=[O:32])[CH:17]([CH2:29][C:30]#[CH:31])[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:2]=[N-:3].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:21]([O:20][C:19]([NH:18][CH:17]1[CH2:29][C:30]2=[CH:31][N:1]([N:2]=[N:3]2)[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:42])[CH2:9][CH2:10][CH:11]([C:38]([O:40][CH3:41])=[O:39])[NH:12][C:13](=[O:37])[CH:14]([CH2:33][CH:34]([CH3:35])[CH3:36])[NH:15][C:16]1=[O:32])=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)NC(CCC(=O)NCCCN=[N+]=[N-])C(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)C1CCC(=O)NCCCn2cc(nn2)CC(NC(=O)OCc2ccccc2)C(=O)NC(CC(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
To a solution of compound 10 (0.3 g: 0.512 mmol) in dry DCM (420 mL) under N2 atmosphere, was added DBU (0.233 g; 1.53 mmol) at room temperature with vigorous stirring. After 15 min, Cu(I)Br (0.073 g; 0.512 mmol) was added and the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was quenched by adding 3M HCl (100 mL) and the aqueous layer was separated and extracted with DCM (2×500 mL). The combined organic layers were washed with brine (300 mL), and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give a crude product which was purified using flash chromatography (silica gel; methylene chloride/methanol 99:1) to give compound 11 as a white solid (0.14 g; 45% yield). 1H NMR (DMSO-d6) δ 8.5 (s, 1H), 8.1 (s, 1H), 7.5 (s, 1H), 7.3 (m, 5H), 5.0 (m, 2H), 4.3 (m, 1H), 4.1 (m, 2H), 3.6 (m, 2H), 3.3 (s, 3H), 3.11 (m, 2H), 2.88 (m, 2H), 2.98-2.24 (m, 5H), 1.49-1.8 (m, 5H), 0.86 (m, 6H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([O-:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Na+].[F:19][C:20]([F:41])([F:40])[C:21]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:29][CH:28]=1)([OH:26])[C:22]([F:25])([F:24])[F:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:37]3[CH2:38][CH2:39][N:34]([CH2:33][C:30]4[CH:31]=[CH:32][C:27]([C:21]([OH:26])([C:22]([F:23])([F:24])[F:25])[C:20]([F:41])([F:19])[F:40])=[CH:28][CH:29]=4)[CH2:35][CH2:36]3)=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=C(Cc1ccc(C(=O)[O-])cc1)NCC1CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1)NCC1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 1.9 %

Procedure:
Sodium 4-(2-(cyclopropylmethylamino)-2-oxoethyl)benzoate (5.26 mmol, 1.342 g), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (5.26 mmol, 1.800 g), and triethylamine (18.40 mmol, 2.56 mL, 1.862 g) were combined in dichloromethane (25 mL) and the reaction mixture stirred at room temperature for 15 minutes. 1-Propanephosphonic acid cyclic anhydride (7.89 mmol, 4.69 ml, 5.02 g; 50% solution in ethyl acetate) was added dropwise and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer was separated and concentrated under vacuum to obtain crude product. The crude product was purified by SCX column chromatography, silica column chromatography (eluting with 90:10:1 dichloromethane/methanol/ammonia) and acidic preparative HPLC to afford the title compound (55.3 mg). MS (ESI) m/z 558.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@@H:38]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH:40]([OH:45])[C:41]([F:44])([F:43])[F:42])[C:34]([F:50])=[CH:33][N:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:43][C:41]([F:42])([F:44])[CH:40]([OH:45])[CH2:39][C@@H:38]([NH:37][C:35]1[C:34]([F:50])=[CH:33][N:32]=[C:31]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH:9]=2)[N:36]=1)[C:46]([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)[C@@H](CC(O)C(F)(F)F)Nc1nc(Cl)ncc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](CC(O)C(F)(F)F)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A solution of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.091 g, 0.218 mmol), 7a, (4R)-4-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-1,1,1-trifluoro-5,5-dimethyl-hexan-2-ol, 180a, (0.060 g, 0.182 mmol) and K3PO4 (0.116 g, 0.546 mmol) in 2-methyl THF (5 mL) and H2O (1.5 mL) was degassed under a stream of nitrogen for 45 minutes. To the reaction mixture was added X-phos (0.010 g, 0.022 mmol) and Pd2(dba)3 (0.004 g, 0.005 mmol). The reaction mixture was stirred at 120° C. in a pressure tube for 2 hours. The aqueous phase was removed. The organic phase was filtered through a pad of celite and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (40% EtOAc/Hexanes) to afford 60 mg of the desired product: 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.37 (dd, J=8.9, 2.8 Hz, 1H), 8.24 (t, J=8.7 Hz, 1H), 8.16 (d, J=2.9 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 4.92 (t, J=7.8 Hz, 2H), 4.44 (t, J =10.3 Hz, 1H), 4.06 (s, 1H), 2.34 (s, 3H), 2.13 (dt, J=13.6, 4.9 Hz, 1H), 1.66 (dd, J=23.0, 9.3 Hz, 1H), 1.07 (d, J=8.4 Hz, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=4.02 min (M+H) 584.41.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([C:60]([N:62]2[CH2:66][CH2:65][C@H:64]([CH2:67][N:68]3[CH2:72][CH2:71][CH2:70][CH2:69]3)[CH2:63]2)=[O:61])[CH2:43]1>CN(C)C=O.C(N(C(C)C)CC)(C)C>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:19]2[C:20]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])=[C:16]([S:41][C@@H:42]3[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=4)=[O:48])[C@H:44]([C:60]([N:62]4[CH2:66][CH2:65][C@H:64]([CH2:67][N:68]5[CH2:69][CH2:70][CH2:71][CH2:72]5)[CH2:63]4)=[O:61])[CH2:43]3)[C@H:17]([CH3:40])[C@H:18]12)[CH3:37]
Reactant: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](CN2CCCC2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](CN5CCCC5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 20 h

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (225 mg) in anhydrous dimethylformamide (3 ml), a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3R)-3-(pyrrolidin-1-ylmethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (198 ml) in anhydrous dimethylformamide (1 ml) and diisopropylethylamine (97 μl) were added in an ice bath. The resulting mixture was stirred for 20 hours at the same temperature. The reaction mixture was concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate. The resulting mixture was washed successively with water and saturated saline solution and dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was subjected to chromatography through a silica gel column and from the fraction eluted with ethyl acetate/methanol=4/1, 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3R)-3-(pyrrolidin-1-ylmethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (235 mg) was obtained as a powder.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][NH:14][CH2:15]2)=[CH:10][C:9]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:6].CCN(C(C)C)C(C)C.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:40]Cl.O>CN(C=O)C.C(OCC)(=O)C>[CH2:5]([O:7][C:8]1[CH:17]=[C:16]2[CH:11]([CH2:12][CH2:13][N:14]([CH2:40][C:39]3[CH:42]=[C:43]([O:47][CH3:48])[C:44]([O:45][CH3:46])=[C:37]([O:36][CH3:35])[CH:38]=3)[CH2:15]2)[CH2:10][C:9]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:6]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: CCOc1cc2c(cc1OCc1ccccc1)CCNC2
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC1=C(OCc2ccccc2)CC2CCN(Cc3cc(OC)c(OC)c(OC)c3)CC2=C1

Procedure:
A solution of 7-ethoxy-6-benzyloxytetrahydroisoquinoline acetate (293 mg, 0.86 mmol), Hunig's base (0.325 mL, 1.96 mmol) and 3,4,5-trimethoxybenzyl chloride (247 mg, 1.14 mmol) in DMF (8 mL) were heated to 80° C. overnight. Water and ethyl acetate (50 mL each) were then added to the cooled solution, the organic layer separated and washed with water (5×), brine, dried and evaporated. The desired product was isolated by column chromatography (3:2 hexane/ethyl acetate) to give the product as a clear colourless oil (340 mg, 85%) which showed 1H NMR δ 1.41 (3H, t, J 7.0), 2.63-2.80 (4H, m), 3.54 (2H, s), 3.58 (2H, s), 3.84 (3H, s), 3.84 (6H, s), 4.03 (2H, q, J 7.0), 5.09 (2H, s), 6.54 (1H, s), 6.61 (2H, s), 6.65 (1H, s) and 7.26-7.44 (5H, m). m/z HRMS [ES+] found 464.2413, C28H34NO5 (M++H) requires 464.2437.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][CH:27]=[N:26][C:25]=2[C:29](O)=[O:30])=[CH:20][CH:19]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:29]([C:25]3[N:26]=[CH:27][O:28][C:24]=3[C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)=[O:30])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Reactant: O=C(O)c1ncoc1-c1ccc(F)cc1
Product: CC(F)(F)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccc(F)cc3)n2)o1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(4-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]([CH3:45])([CH2:43][CH3:44])[CH2:10][C:11]1[N:12]=[C:13]([CH:23]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=3)=[CH:27][CH:26]=2)[N:14](C(OC(C)(C)C)=O)[CH:15]=1>>[CH3:8][C:9]([CH3:45])([CH2:43][CH3:44])[CH2:10][C:11]1[N:12]=[C:13]([CH:23]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=3)=[CH:27][CH:26]=2)[NH:14][CH:15]=1
Reactant: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(Cc2ccc(-c3ccc(F)cn3)cc2)NS(C)(=O)=O)n1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(-c3ccc(F)cn3)cc2)NS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 mL) was added to neat tert-butyl 4-(2,2-dimethylbutyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-[(methylsulfonyl)amino]ethyl}-1H-imidazole-1-carboxylate. After stirring at ambient temperature for 1 h, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Preparatory plate chromatography eluting with 100% ethyl acetate afforded the title compound. (M+H) found: 445.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][O:21][C:22](=[O:39])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])=[O:18].[C:40](Cl)(=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>C(OCC)C>[C:40]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][O:21][C:22](=[O:39])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:2](=[O:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:18])(=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=C(CCCCCCCCCCCCCCCO)OCOC(=O)CCCCCCCCCCCCCCCO
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)OCOC(=O)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC
Yield: 88 %

Procedure:
A mixture of methylene bis(16-hydroxyhexadecanoate) (1.0 mmol) and palmitoyl chloride (7.0 mmol) was refluxed in diethyl ether (10 ml) for 24 hours before the solvent was evaporated. The residual material was purified on a silica gel flash column eluting first with hexane/chloroform (2:1) and then with chloroform. Yield 88%, white solid. 1H NMR (CDCl3): δ 0.88 (6 H, t, J 6.7 Hz), 1.2-1.4 (92 H, m), 1.5-1.7 (12 H, m), 2.28 (4 H, t, J 7.5 Hz), 2.35 (4 H, t, J 7.6 Hz), 4.05 (4 H, t, J 6.7 Hz), 5.75 (2 H, s). 13C NMR (CDCl3): δ 14.11, 22.70, 24.64, 25.06, 25.97, 28.70, 29.04, 29.19, 29.25, 29.29, 29.38, 29.47, 29.50, 29.56, 29.62, 29.67, 29.70, 29.71, 31.94, 34.00, 34.43, 64.39, 79.06, 172.59, 173.97.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].[CH:30]1(B(O)O)[CH2:32][CH2:31]1.[F-].[K+].[Br-].[Na+]>O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([CH:30]4[CH2:32][CH2:31]4)=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cncn1C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: [Br-]
Agent: [F-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1cncn1C1CCCc2cc(C3CC3)ccc21
Temperature: 90 °C

Procedure:
A flask is charged with 3-(6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester (0.183 g, 0.426 mmol), which can be prepared as described in Example 48, cyclopropylboronic acid (0.091 g, 1.059 mmol), potassium fluoride (0.081 g, 1.39 mmol), sodium bromide (0.043 g, 0.423 mmol) and toluene (5 mL). Tetrakis(triphenylphosphine) palladium (0.015 g, 0.013 mmol) is added and the mixture is heated to 90° C. overnight. The reaction is cooled to room temperature, diluted with water and extracted with dichloromethane. The organic phase is dried over Na2SO4, filtered, and concentrated to give a residue, which is purified by silica gel chromatography (elution with hexanes-ethyl acetate mixtures) to give 3-(6-cyclopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 325.2 (M+H)+. The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(6-cyclopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; 1H NMR (400 MHz, MeOD) δ ppm 0.71-0.75 (m, 2 H), 1.00-1.05 (m, 2 H), 1.43 (d, J=6.3 Hz, 3 H), 1.46 (d, J=6.3 Hz, 3 H), 1.65-1.76 (m, 1 H), 1.87-1.98 (m, 2 H), 2.24-2.39 (m, 2 H), 2.87 (ddd, J=16.9, 9.3, 5.3 Hz, 1 H), 3.00 (dt, J=16.9, 5.0 Hz, 1 H), 5.34 (sept, J=6.3 Hz, 1 H), 6.51 (t, J=4.8 Hz, 1 H), 6.98 (dd, J=9.3, 1.2 Hz, 1 H), 7.03 (d, J=9.3 Hz, 2 H), 8.32 (d, J=1.5 Hz, 1 H), 8.51 (d, J=1.0 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.C(OCC)(=O)C.O.CCCCCC.CN(C=O)C>[Si:13]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C(=O)O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-hydroxy-4-methoxybenzoic acid (6.726 g, 40 mmol), tert-butyldimethylsilyl chloride (13.26 g, 88 mmol), imidazole (10.893 g, 160 mmol) and DMF (40 mL) was stirred at room temperature for 18 hr. Hexane was added and the resulting mixture washed with water. The aqueous layer was reextracted two times with hexane and the extracts added to the hexane layer from the first extraction. The combined extracts were washed with small amount of water. During the washing some precipitate formed. The organic phase, together with the precipitate, was dissolved in small amount of methanol and rotary evaporated. The residue was taken into methanol (100 ml) and stirred at room temperature with potassium carbonate (10 g) and water (3 ml) for 1.5 hr. A mixture of ethyl acetate and crushed ice was added and the mixture was carefully acidified with dilute hydrochloric acid (the final pH of the aqueous layer was 3.5). The organic phase was separated and the aqueous layer extracted two times with ethyl acetate. The combined extracts were washed with a mixture of brine and water (1:1) and dried. TLC (silica gel, hexane/ethyl acetate=2:1) of the product gave one spot having an Rf of 0.2. NMR(δ): 0.18 (s, 6H), 1.00 (s, 9H), 3.90 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2].C([Li])(C)(C)C.[Cl:23]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.CCCCC.CCOCC>[Cl:23][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCOc1ncccc1NC(=O)OC(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCC
Product: CCOc1nccc(Cl)c1NC(=O)OC(C)(C)C
Temperature: -60 °C

Procedure:
To a solution of 15 g (63 mmol) of t-butyl N-(2-ethoxy-3-pyridinyl)carbamate in 175 mL of dry tetrahydrofuran was added with stirring at -60° C., 78 mL (132 mmol) of 1.7M t-butyl lithium in pentane. The resulting solution was allowed to warm to -10° C. over a 30 min. period and was then cooled to -60° C. A A 22.3 g (94 mmol) amount of hexachoroethane was added all at once with stirring and the mixture are allowed to warm to ambient temperature. It was then diluted with 600 mL of ether and the resulting solution was washed with 150 mL of water, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by column chromatography to obtain 11.1 g (65 percent of theory) of the title compound as a colorless solid melting at 73°-74° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[N:7][CH:8]=1.[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[C:11]=2[N+:20]([O-:22])=[O:21])[N:6]=[N:7][CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cnnc(Oc2c([N+](=O)[O-])c(C(F)(F)F)nn2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
5-Methoxy-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (Compound No. 5, 1.2 g, 0.0043 mole) was added to a mixture of nitric acid (5 mL) and sulfuric acid (13 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice and neutralized with 10% sodium hydroxide. Filtration gave, after drying, 5-methoxy-3-[[1-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (1.36 g, 99% yield) as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH:24]=1
Reactant: COc1ccccc1-c1cccc(C=O)c1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1-c1cccc(CN2CCN(c3ccccc3OC)CC2)c1

Procedure:
103 mg of the target compound (0.27 mmol, 56.4%) was obtained using 1-(2-methoxyphenyl)piperazine (181 mg, 0.94 mmol), 2′-methoxybiphenyl-3-carbaldehyde (100 mg, 0.47 mmol) and NaBH(OAc)3 (303 mg, 1.41 mmol) according to the synthesis method of Compound 1.