Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:50]([F:53])([F:52])[F:51])=[C:13]([N:15]2[C:19](=[O:20])[N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[S:34](=[O:44])(=[O:43])[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:24][C:23]=3[F:45])[C:17]([CH2:46][CH2:47][CH2:48][CH3:49])=[N:16]2)[CH:14]=1>>[C:39]([O:38][C:36]([NH:35][S:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:18]2[C:17]([CH2:46][CH2:47][CH2:48][CH3:49])=[N:16][N:15]([C:13]3[CH:14]=[C:9]([NH:8][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH:10]=[CH:11][C:12]=3[C:50]([F:52])([F:53])[F:51])[C:19]2=[O:20])=[C:23]([F:45])[CH:24]=1)(=[O:44])=[O:43])=[O:37])([CH3:40])([CH3:41])[CH3:42]
Reactant: CCCCC(=O)Cl
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Product: CCCCC(=O)Nc1ccc(C(F)(F)F)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)OC(C)(C)C)cc3F)c2=O)c1
Yield: 91 %

Procedure:
Valeryl chloride was reacted with 2-[5-amino-2-(trifluoromethyl)phenyl]-4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 33, Step D) according to the procedure of Example 26 to give a 91% yield of the title compound as a white solid, mp 179°-182° C.; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 754 (M+Li)+.
Reaction SMILES: CC1N(S(O)(=O)=[O:7])C(=O)C1.C(N(CCCC)CCCC)CCC.ON1C2C=CC=CC=2N=N1.[CH:34]1([N:40]=[C:41]=[N:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:41]([NH:40][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)([NH:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:7]
Reactant: CC1CC(=O)N1S(=O)(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
[3S-[3α(Z),4β]]-3-[[(2-Amino-4-thiazolyl)-](1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzotriazole and 0.05 g of 4-dimethylaminopyridine were dissolved in 20 ml of dimethylformamide and a solution of 1.06 g of dicyclohexylcarbodiimide in 5 ml of dimethylformamide was added. After stirring for 15 minutes at room temperature, a solution of 0.94 g Girard Reagent P in 20 ml of dimethylformamide was added. After 3 hours of stirring, formed dicyclohexylurea was filtered off and the dimethylformamide of the filtrate was distilled off. Addition of 50 ml of tetrahydrofuran to the residue yielded 1.8 g of crude product, which was purified by column chromatography on HP-20 using water as an eluent, yielding 0.63 g of product, melting point 235° C.
Reaction SMILES: CCN(CC)CC.[Cl:8][CH2:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:22]/[O:23][CH3:24])/[C:19](Cl)=[O:20])[N:17]=1)=[O:11].[NH2:25][CH:26]1[C:55](=[O:56])[N:28]2[C:29]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:30]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:31]([CH3:33])[S:32][C@H:27]12>C(Cl)Cl>[Cl:8][CH2:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:22]/[O:23][CH3:24])/[C:19]([NH:25][CH:26]2[C:55](=[O:56])[N:28]3[C:29]([C:39]([O:41][CH:42]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)=[O:40])=[C:30]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:31]([CH3:33])[S:32][C@H:27]23)=[O:20])[N:17]=1)=[O:11]
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2S[C@H]1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(C)=O)[C@H](C)S[C@H]12)c1csc(NC(=O)CCl)n1
Reaction time: 0.75 h
Yield: 59.6 %

Procedure:
A 0.5 ml portion of Et3N, along with 1.13 g of 2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetyl chloride, was added to a solution of 1.6 g of diphenylmethyl 7-amino-2β-methyl-3-acetoxymethylceph-3-em-4-carboxylate in 50 ml of CH2Cl2 at -40° C., and the mixture was stirred at from -20° C. to -15° C. for 45 minutes. The reaction solution was washed with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl solutions, and dried over MgSO4, followed by distilling off the CH2Cl2 under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.AcOEt (5:1) were collected to distill off the solvent, thus yielding 1.5 g (61%) of diphenylmethyl 7-[2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-2β-methyl-3-acetoxymethylceph-3-em-4-carboxylate.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH:6]([CH3:9])[CH2:7][CH3:8])[CH2:3][CH3:4].[Cl:10][SiH:11]([Cl:13])[Cl:12].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>>[CH3:1][CH:2]([CH:5]([Si:11]([Cl:13])([Cl:12])[Cl:10])[CH:6]([CH3:9])[CH2:7][CH3:8])[CH2:3][CH3:4]
Reactant: Cl[SiH](Cl)Cl
Reactant: CCC(C)=CC(C)CC
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CCC(C)C(C(C)CC)[Si](Cl)(Cl)Cl
Yield: 58.3 %

Procedure:
A one-liter autoclave equipped with a stirrer was charged in a nitrogen atmosphere with 76 grams (0.60 mol) of 3,5-dimethyl-3-heptene, 161 grams (1.2 mol) of trichlorosilane and 29 grams (0.12 mol) of 1,1'-azobis(cyclohexane-1-carbonitrile) and the mixture was reacted at a temperature of 130° C. for 5 days. The resulting reaction mixture was purified by distillation thereby obtaining 92 grams (0.35 mol) of 3,5-dimethyl-4-trichlorosilylheptane. The structure of the resulting product was identified by 1H-NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[C:17]=1[O:24][CH3:25].[Cl-].[Al+3].[Cl-].[Cl-].COC1C=CC(OC)=CC=1C(C1C=C(OC)C=C(OC)C=1)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[C:17]([O:24][CH3:25])[C:18]=2[OH:22])=[O:7])[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: COc1cccc(OC)c1OC
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Agent: COc1cc(OC)cc(C(=O)c2cc(OC)ccc2OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2O)c1
Yield: 50.4 %

Procedure:
3,5-Dimethoxybenzoyl chloride (5.19 g, 25.87 mmol), 1,2,3-trimethoxybenzene (4.35 g, 25.87 mmol) in anhydrous methylene chloride (40 ml), and aluminum chloride (3.79 g, 28.45 mmol) were treated in the same manner as described above for the synthesis of (2,5-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanone. The crude material was purified via flash column chromatography (20% EtOAc in hexane) to give (3,5-dimethoxy-phenyl)-(2-hydroxy-3,4-dimethoxy-phenyl)-methanone as a yellow solid (4.15 g, 50%); 1HNMR (CDCl3) δ 12.36 (s, 1H, OH), 7.42 (d, J=9 Hz, 1H, Ar), 6.75 (d, J=2 Hz, 2H, Ar), 6.64 (t, J=2 Hz, 1H, Ar), 6.47 (d, J=9 Hz, 1H, Ar), 3.94 (s, 6H, 2OCH3), 3.84 (s, 6H, 2OCH3); 13C NMR (CDCl3) δ 200.4, 160.7, 158.9, 158.0, 140.1, 136.9, 130.3, 114.6, 107.0, 103.8, 102.9, 60.9, 56.3, 55.7; Anal. Calcd. For C17H18O6: C, 64.14; H, 5.70. Found: C, 64.29; H, 5.42; N, <0.05. The product was carried over to the next step.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[CH:48]=[N:47][C:46]([CH3:49])=[C:45]2[NH:50][CH:51]=[CH:52][C:44]=12>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].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>[CH3:40][C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:12][C:11]([C:43]4[CH:48]=[N:47][C:46]([CH3:49])=[C:45]5[NH:50][CH:51]=[CH:52][C:44]=45)=[N:10][C:9]=3[CH:26]=2)[CH2:31][CH2:32]1)([CH3:41])[C:37]([NH2:39])=[O:38]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: Cc1ncc(Br)c2cc[nH]c12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(C)(C)C(N)=O)CC4)cc3n2)c2cc[nH]c12
Yield: 46.8 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]isobutyramide (197 mg, 0.28 mmol), 4-bromo-7-methyl-1H-pyrrolo[2,3-c]pyridine (60 mg, 0.28 mmol), copper(I) 2-thiophene carboxylate (11 mg, 0.056 mmol), and Pd(PPh3)4 (32 mg, 0.028 mmol) in dioxane (3 mL) was placed in a microwave tube which was sealed and evacuated. The reaction vessel was degassed and purged with argon (×3). The reaction mixture was irradiated at 140° C. for 20 min. The cooled mixture was then poured onto an Isolute® SCX-II cartridge and the cartridge was washed with MeOH (100 mL). The product was eluted with 2 M NH3 in MeOH. The pooled fractions were evaporated and the product was further purified by chromatography on silica (Si—PPC), using MeOH in DCM (0-10%) as eluent. The pooled product-containing fractions were evaporated and the residue was crystallized from hot EtOAc to afford 132 as a white crystalline solid (70 mg, 46%). LCMS: (Method F): RT 5.02 min; [M+H]+ 535.2. 1H NMR (DMSO, 400 MHz): δ 11.71 (s, 1 H); 9.02 (s, 1 H); 7.66 (t, J=2.7 Hz, 1 H); 7.44 (s, 1H); 7.38 (dd, J=2.9, 1.9 Hz, 1 H); 7.08 (d, J=3.5 Hz, 1 H); 6.95 (d, J=3.5 Hz, 1 H); 3.99 (t, J=4.6 Hz, 4 H); 3.86 (s, 2 H); 3.85-3.80 (m, 4 H); 2.73 (s, 3 H); 2.62-2.53 (m, 4 H); 2.47 (s, 4H); 1.08 (s, 6 H)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C=O)C>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ncnc2c1ccn2C1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
NaH (3.8 g, 95.3 mmol) was added to a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (10 g, 63.5 mmol) in DMF (50 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min, then warmed to room temperature. At this time Cyclopentylbromide (18.9 g, 127 mmol) was added and the reaction was heated to 60° C. After 4 h the reaction was cooled to 0° C. and quenched with water. The aqueous layer was extracted with EtOAc (3×), the combined organic layers were washed with water (1×), dried over Na2SO4, and concentrated. Purification by flash column chromatography (Hexanes/Ethyl acetate 9:1) afforded the title compound as a clear oil (10.6 g, 75%). MS: 222.1/224.1 (MH+); HPLC Rf: 5.77 min. (HPLC method 4).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)C(C(O)=O)=[CH:9]1>C(Cl)Cl>[CH3:9][N:8]1[C:16]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:7]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1cc(C(=O)O)c2ccccc21
Solvent: ClCCl
Product: Cn1cc(C(=O)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxalyl chloride (11.86 mL, 136 mmol) was added dropwise to a solution of 1-methyl-1H-indole-3-carboxylic acid (4.76 g, 27 mmol) in 100 mL of methylene chloride. A rapid evolution of gas was observed. The reaction stirred at room temperature for 17 h (overnight). The solvent was removed under reduced pressure to give a pink solid To remove any excess oxalyl chloride the solid was dissolved in benzene and the solvent removed under reduced pressure to give 1-methyl-1H-indole-3-carbonyl chloride which was immediately used in step 2 without additional purification.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]C)=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][NH2:21].O>CO>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([NH:20][NH2:21])=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCN(C(=O)c2ccccc2)CC1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of (±)-methyl 1-benzoyl-4-piperidinecarboxylate (502 mg, 2.03 mmol) in MeOH (10 mL) was added hydrazine hydrate (1.6 mL). After stirring for 24 h at rt, the reaction mixture and water (40 mL) was added. After washing with Et2O (2×20 mL), the aqueous layer was evaporated off under vacuo. The title compound was obtained as an amorphous beige solid (469 mg, 93%) in a 91.0% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([OH:13])=O.Cl.[NH:19]1[CH2:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([N:19]1[CH2:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20]1)=[O:13]
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: COc1cn[nH]c1-c1cc(C(=O)O)ccc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cn[nH]c1-c1cc(C(=O)N2CC(c3ccc(C#N)cc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 244.7, 60 mg, 0.26 mmol) in N,N-dimethylformamide (2 mL). 4-(Azetidin-3-yl)benzonitrile hydrochloride (75 mg, 0.39 mmol), EDC.HCl (99 mg, 0.52 mmol), and 4-dimethylaminopyridine (63 mg, 0.52 mmol) were added and the solution was stirred for 2 h at room temperature. The reaction was diluted with EtOAc (30 mL) and washed with brine (3×15 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-010(Waters)): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (35.0% CH3CN up to 50.0% in 10 min, up to 100% in 1 min, down to 35.0% in 2 min); Detector, UV 254 & 220 nm. The fractions contained pure product were combined and lyophilized to obtain the title compound as an off-white solid (44.3 mg, 46%). m/z (ES+) 373 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:18][CH:19]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:21](=[O:22])[CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:24])([F:12])[F:25])[CH:15]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]ccc1C
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2cccc(C(F)(F)F)c2)c1C

Procedure:
3-Methyl-4-[2-(3-trifluoromethylphenyl)-acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (103) was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-trifluoromethylphenyl)-acetyl chloride following the procedure described in Example 32. Crude yield: 97%. 1H-NMR (400 MHz, CDCl3): δ 1.38 (t, 3H), 2.62 (s, 3H), 4.11 (s, 2H), 4.35 (q, 2H), 7.45 (m, 2H), 7.51 (m, 3H), 9.40 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ 11.73, 14.40, 46.73, 60.78, 123.70, 124.70, 126.82, 128.93, 129.71, 133.01, 135.85, 161.61, 192.58 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.73, 14.40; CH2 carbons: 46.73, 60.78; CH carbons: 123.70, 126.82, 128.93, 129.71, 133.01 ppm. LC/MS: 79.18%, m/z=339.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1O.CI>CC(C)=O>[Br:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:4][CH3:1]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1Br
Temperature: 25 °C

Procedure:
A mixture of K2CO3 (68 g, 0.5 mol), 2-bromo-4-chorophenol (50 g, 0.24 mol) and MeI (42.6 g, 0.3 mol) in acetone (1000 mL) was heated to reflux for 5 h and then cooled to room temperature. The solid was filtered off and washed with dichloromethane (100 mL×3). The combined filtrate was concentrated to dryness. The residue was diluted with diethyl ether (500 mL) and washed HCl (1 M, 100 mL×2), H2O (100 mL×2) and brine (200 mL). The separated organic layer was dried over Na2SO4 and concentrated to give 2-bromo-4-chloroanisole 5a as light yellow liquid. 1H NMR (CDCl3): δ 7.52 (d, J=2.8 Hz, 1H), 7.24 (q, J1=8.8 Hz, J2=2.8 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CC(C)=O>[Cl:7][C:8]1[N:12]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Clc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Cn1c(Cl)nc2ccccc21
Yield: 88.5 %

Procedure:
In a round bottomed flask are added K2CO3 (9.34 g, 67.7 mmol), 2-chlorobenzimidazole (5.16 g, 33.8 mmol) and tert-butyl bromoacetate (6.6 g, 5 ml, 33.8 mmol) in acetone (100 ml). The resulting suspension is refluxed for 1 h. The crude mixture is filtered through a filter paper and water (100 ml) is added. The resulting aqueous phase is extracted three times with Et2O. The combined organic phases are washed with brine and dried over MgSO4. The solvent is evaporated under reduced pressure yielding the title compound (7.98 g) in 88% as a white powder: tR=2.20 min (LC-2), ESI-MS (pos.): m/z 267.2 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.48 (s, 9H, tBu), 4.92 (s, 2H, CH2CO2), 7.24-7.40 (m, 3Harom), 7.76-7.80 (m, 1Harom). Intermediate 2-IIa and 2-IIb tert-Butyl (2-chloro-5-nitro-benzoimidazol-1-yl)-acetate and its 6-nitro regioisomer are prepared according to the same procedure (yield 93%): tR=6.68 min (LC-1), ESI-MS (pos.): m/z 312.08 [M+H]+, 310.28 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 1.50 (s, 9H, tBu), 1.52 (s, 9H, tBu), 5.04 and 5.06 (s, 2H, CH2CO2), 7.38 (d, 1Harom), 7.86 (d, 1 Harom), 8.32-8.40 (m, 3Harom), 8.96 (m, 1Harom).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C([O-])([O-])=O.[Na+].[Na+].[CH2:24]([CH2:27]OC)OC>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>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:4]2[CH:3]=[C:2]([C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][C:24]=3[CH3:27])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=2)[CH2:12][CH2:13]1
Reactant: COCCOC
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A mixture of 200 mg (0.666 mmol) 1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in the previous step), 136 mg (0.999 mmol) and 77.0 mg (0.0666 mmol) of tetrakis(triphenylphosphine)palladium (0) under Ar was added 4.0 mL of degassed dimethoxyethane (DME) and 400 μL (0.799 mmol) of 2.0 M aq Na2CO3. The mixture was heated with stirring under Ar at 80° C. for 14 h. The cooled (RT) mixture was concentrated and chromatographed on a 10-g silica SPE column with 1-5% MeOH in dichloromethane-hexane (1:1). The product fractions were treated with 80 mg of decolorizing carbon, filtered, concentrated, and then rechromatographed on a similar column with 1-3% EtOH-dichloromethane to afford 265 mg of the title compound as a yellow resin (75% purity by 1H-NMR as a mixture with triphenylphosphine) that was used in the following reaction without further purification: Mass spectrum (ESI, m/z): Calcd. for C11H21N3O3, 312.2 (M+H). found 312.2.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[B:17](OCC)([O:21]CC)[O:18]CC>C1COCC1>[CH2:1]([B:17]([OH:21])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC[Mg]Cl
Reactant: CCOB(OCC)OCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCB(O)O
Temperature: -20 °C
Yield: 93 %

Procedure:
To a stirred solution of tetradecylmagnesium chloride (50 ml, 1M in THF) was added at −20° C. to THF (50 ml) followed by triethyl borate (10.2 ml, 60 mmol). The reaction mixture was stirred briefly at −20° C., and warmed up slowly over 3 hours to room temperature. Most of the solvent was removed on rotary evaporator and the concentrated mixture was poured into water (300 ml) and pH of the mixture was adjusted to about pH 4 using 12N hydrochloric acid. After being stirred for 10 hours, precipitated tetradecylboronic acid was isolated by filtration, washed three times with water and dried with air overnight. The dried white solid was washed with cold hexane to remove a trace of tetradecane and dried with air to yield 11.3 g (93%) of n-tetradecylboronic acid.
Reaction SMILES: [I-:1].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18]OS(C)(=O)=O)[CH2:14][CH2:13]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CC(C)=O>[C:3]([O:7][C:8]([NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][I:1])[CH2:14][CH2:13]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CI)CC1

Procedure:
In 130 ml of anhydrous acetone was dissolved 13.24.g of trans-N-t-butoxycarbonyl-4-methanesulfonyloxymethylcyclohexylmethylamine, and 12.32 g of sodium iodide was added thereto, and the resulting mixture was heated under reflux for 3 hours and 45 minutes. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was washed successively with an aqueous sodium thiosulfate solution and an aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluting solvent: cyclohexane/ethyl acetate=4/1) to obtain a pale yellow crystalline solid. The crystalline solid was recrystallized from hexane to obtain 13.67 g of the desired compound as a colorless crystalline solid.