Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][N:3]=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.CC1(C)CCCC(C)(C)N1.C([Li])CCC>C1COCC1.O>[F:1][C:2]1[C:7]([B:18]([OH:23])[OH:19])=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=2)[CH3:9])=[CH:4][N:3]=1
Reactant: CSc1ccc(C(C)c2ccc(F)nc2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(C(C)c2cnc(F)c(B(O)O)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
2-Fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridine (1.078 g, 4.359 mmol) and triisopropyl borate (2.50 mL, 10.9 mmol) were dissolved in THF (11.5 mL). In a separate flask, 2,2,6,6-tetramethylpiperidine (1.11 mL, 6.54 mmol) was dissolved in THF (12 mL) and the flask was cooled in an ice water bath. Then, n-butyllithium solution (1.6 M in hexanes, 3.8 mL, 6.1 mmol) was added via syringe, and the yellow solution was stirred under nitrogen for 15 min. Then, the contents were transferred via syringe to the other flask, which was pre-cooled in a dry ice/acetone bath. After completing the transfer, the reaction was stirred under nitrogen at −78° C. for 1 h. Then, the reaction was allowed to slowly warm up to room temperature while being stirred overnight. The reaction was treated with water (30 mL) and stirred for about 30 min. The layers were separated, and the organic phase was extracted with 1 N aqueous NaOH (15 mL). The organic phase was discarded, and the aqueous phase was treated with aqueous 5N HCl to lower the pH to around 5-6. The aqueous phase was extracted with 10:1 DCM/MeOH. The extracts were combined, concentrated, and dried under high vacuum to afford 2-fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridin-3-ylboronic acid (1.2342 g). 1H NMR (400 MHz, CDCl3) δ 8.17-8.05 (m, 2H), 7.25-7.19 (m, 2H), 7.15-7.10 (m, 2H), 4.16 (q, J=7.37 Hz, 1H), 2.47 (s, 3H), 1.66 (d, J=7.24 Hz, 3H). m/z (ESI, +ve ion) 292 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10]N=[CH:8][CH:7]=2)=[CH:2]1.I[C:13]1[CH:18]=CC(CCC)=[CH:15][CH:14]=1.O1C=CC(B(O)O)=C1>>[CH2:13]([C:18]1[CH:10]=[CH:11][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:7][CH:8]=1)[CH2:14][CH3:15]
Reactant: c1cc(-c2ccoc2)ccn1
Reactant: CCCc1ccc(I)cc1
Agent: OB(O)c1ccoc1
Product: CCCc1ccc(-c2ccoc2)cc1

Procedure:
As described in Example 1(d) for the preparation of 4-furan-3-yl-pyridine, 1-iodo-4-propylbenzene (500 mg, 2.03 mmol) was coupled to 3-furanboronic acid to furnish in high yield 3-(4-propylphenyl)-furan as a light brown oil that was unstable and used immediately without further purification. 1H NMR (CDCl3): ∂ 7.69 (t, 1H, J=0.9 Hz), 7.46 (t, 1H, J=1.7 Hz), 7.40 (d, 2H, J=8.1 Hz), 7.18 (d, 2H, J=7.8 Hz), 6.68 (t, 1H, J=0.9 Hz), 2.59 (t, 2H, J=7.5 Hz), 1.66-1.60 (m, 2H), 0.95 (t, 3H, J=7.5 Hz).
Reaction SMILES: CC([O-])=O.[K+].[Cl:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[C:17]([NH:22][CH2:23][CH3:24])=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[C:11]([CH3:25])[CH:10]=[C:9]([Cl:26])[N:8]=1.[Br:27]Br.O>CC(O)=O>[Br:27][C:20]1[CH:21]=[C:16]([C:14]([NH:13][C:12]2[C:7]([Cl:6])=[N:8][C:9]([Cl:26])=[CH:10][C:11]=2[CH3:25])=[O:15])[C:17]([NH:22][CH2:23][CH3:24])=[N:18][CH:19]=1
Reactant: CCNc1ncccc1C(=O)Nc1c(C)cc(Cl)nc1Cl
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCNc1ncc(Br)cc1C(=O)Nc1c(C)cc(Cl)nc1Cl
Reaction time: 0.5 h

Procedure:
Solid KOAc (22.2 g, 229 mmol) was added to a solution of crude N-(2,6-dichloro-4methyl-3-pyridinyl)-2-(ethylamino)-3-pyridinecarboxamide (61.98 g, <190 mmol) in AcOH (600 mL). A solution of Br2 (9.7 mL, 191 mmol) was then added over 30 min. After stirring 30 min, additional amounts of KOAc and Br2 were introduced until TLC indicated that no starting material remained (a total of 11.2 g of KOAc and 5.91 mL of Br2). The solution was then poured into water (2 L) and stirred for 20 min. The solid was removed by filtration and then dissolved in Et2O (1 L). The ethereal solution was washed with water (3×), aqueous saturated NaHCO3, brine then dried (MgSO4) to give a mixture containing, as the major component, the title compound (77.7 g, yellow foam). The material was used directly in the subsequent reaction.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:27]([CH2:28][CH2:29][C@:11]12[CH3:12])[C@:24]1([CH2:25][OH:26])[C:19](=[CH:20][C:21](=[O:30])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(O)(C)(C)C>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:27]([CH2:28][CH2:29][C@:11]12[CH3:12])[C@:24]1([CH2:25][OH:26])[C:19](=[CH:20][C:21](=[O:30])[CH2:22][CH2:23]1)[CH:18]=[CH:17]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O

Procedure:
17β,19-Dihydroxy-4-androsten-3-one diacetate and chloranil are dissolved in t-butanol which is rapidly brought to reflux. The t-butanol is distilled at atmospheric pressure at such a rate that the total reflux and distillation time equals one hour. The dark residue which remains is triturated with hot chloroform and filtered. The filtrate is extracted with water, a 2% sodium hydroxide solution and again with water. The organic layer is dried over magnesium sulfate and the solvent removed to yield 17β,19-dihydroxy-4,6-androstadien-3-one diacetate. The diene so prepared is refluxed with dichlorodicyanobenzoquinone in anhydrous dioxane for a period of about 48 hours. The mixture is cooled, filtered and the filtrate poured onto a mixture of methylenechloride and water. The organic layer is separated, washed with water, dried well over magnesium sulfate and the solvent removed. The dark residue remaining is chromatographed on silica gel and eluted with methylenechloride to yield from the eluate the desired 17β,19-dihydroxy-1,4,6-androstatrien-3-one diacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[C:38]1([CH2:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:45](=[O:46])[CH2:44][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reactant: O=C(Cl)Cc1ccccc1
Product: CC(C)(Cc1c(C(=O)Cc2ccccc2)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using phenylacetyl chloride in place of trimethylacetyl chloride in Step B.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].Br[C:13]([F:20])([F:19])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15].C([O-])([O-])=O.[Na+].[Na+].O>CC(N(C)C)=O>[F:19][C:13]([F:20])([O:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: CN(C)C(=O)C(F)(F)Br
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)C(=O)C(F)(F)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 33.5 %

Procedure:
A mixture of 2-nitro-5-fluoro-phenol (3.0 g, 19.1 mmol), 2-bromo-2,2-difluoro-N,N-dimethyl-acetamide (3.9 g, 19.1 mmol) and Na2CO3 (2.1 g, 19.8 mmol) in 30 mL of DMAC was heated to 100° C. overnight. The mixture was then poured on 50 mL of H2O and extracted with TBME (2×50 mL). The combined organic layers were washed with 10% NaOH (50 mL) and dried over Na2SO4. The crude product was obtained after evaporation of all volatiles. Purification by chromatography on silica gave the product (1.8 g, 6.4 mmol, 38% yield) as a yellow oil that solidified upon standing.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=O.[CH:11]([NH2:13])=O>>[N:10]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3](=[O:2])[NH:13][CH:11]=1
Reactant: NC=O
Reactant: COC(=O)c1sccc1N
Product: O=c1[nH]cnc2ccsc12
Temperature: 180 °C
Reaction time: 5 h

Procedure:
Methyl-3-aminothiophene-2-carboxylate (15 g, 98.6 m mol) (Matrix, Cat #018289, CAS [22288-78-4]) was dissolved in formamide (50 mL) and stirred at 180° C. for 5 hours. The reaction mixture was further stirred at room temperature for 2 hours and the solid thus obtained was filtered to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=3)[C:10]([C:18]([OH:20])=O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=3)[C:10]([C:18]([Cl:23])=[O:20])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1nccc(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1nccc(-n2nc(C(=O)Cl)c3ccc(I)cc32)n1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carboxylic acid (1.00 g, 2.62 mmol) in DCM (10 mL), was added thionyl chloride (1.9 ml, 26.24 mmol)) followed by a drop of DMF. The mixture was stirred at 50° C. for 45 minutes. The reaction mixture was concentrated in vacuo and DCM (5 mL) was added and the concentration repeated (×2). The crude acid chloride was used directly in the next step: LC-MS m/z=+395.95 (M+H)+(after conversion to methyl ester derivative)
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][NH:11][CH:12]=[O:13].C(N(CC)CC)C.[C:21]1([C:27](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:3]([CH2:8][CH2:9][CH2:10][NH:11][CH:12]=[O:13])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(CCCNC=O)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc(CCCNC=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
To a solution of N-[3-(5-amino-1-methylpyrazol-4-yl)propyl]formamide (3.64 g, 20 mmol) and triethylamine (2.23 g, 22 mmol) in methylene chloride (50 ml) was added triphenylmethyl chloride (6.13 g, 22 mmol). The mixture was stirred at room temperature for 90 minutes. The reaction mixture was washed with successively 10% aqueous citric acid solution, brine, and 10% aqueous sodium carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate and dried in vacuo to give N-[3-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)propyl]formamide (6.8 g) as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][CH:9]([NH:24][C:25]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:8]1=[O:36].[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.[K].CN(C)C=O>O>[C:37]1(=[O:47])[N:41]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][CH:9]([NH:24][C:25]([C:27]3[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[C:8]2=[O:36])[C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCOCCCl)C1=O)c1cc2ccccc2[nH]1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCOCCN2C(=O)c3ccccc3C2=O)C1=O)c1cc2ccccc2[nH]1
Reaction time: 7 h
Yield: 105.3 %

Procedure:
A mixture of (3RS)-1-[2-(2-chloroethoxy)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one (700 mg), potassium phthalimide (610 mg) and N,N-dimethylformamide (5 ml) was stirred for 7 hours at 80°-90° C. The reaction mixture was poured into a cold water (100 ml) and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated to give (3RS)-1-[2-(2-phthalimidoethoxy)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one (0.9 g).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2I)=[O:15])[CH2:10][CH2:9]1.[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2[C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: OB(O)c1ccncc1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(-c2ccncc2)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 7, [4-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-methanone (example 46) was reacted with pyridin-4-yl-boronic acid to give the title compound as light yellow oil. MS: 530.2 (MH+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[C:11](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCCl>[C:11]([N:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[C:4]([O:3][CH3:2])=[O:10])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A solution of 3.00 g (18.1 mmol) of L-proline methyl ester hydrochloride, 5.05 g (18.1 mmol) of trityl chloride and 10 mL of triethylamine in 40 mL of 1,2-dichloroethane is stirred at 22° C. After a few minutes, a thick precipitate began to form. An additional 20 mL of 1,2-dichloroethane is added and the mixture is heated to 60° C. and stirred for 3 hrs. The reaction mixture is partitioned between water (100 mL) and CH2Cl2 (100 mL). The organic layer is washed with satd. NaHCO3 (50 mL), dried (MgSO4) and evaporated. The residue is recrystallized from hexane/EtOAc to give 5.76 g of 1-trityl-pyrrolidine-2-carboxylic acid, methyl ester as a white crystalline solid which is used directly in the next step.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH2:19][OH:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].[H-].[Na+].[CH3:23]I>C1COCC1.[Cl-].[Na+].O>[CH2:1]([C:3]1([CH2:18][CH2:19][O:20][CH3:23])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CCOC)OCC3
Yield: 62.5 %

Procedure:
To a solution of compound 1 (348 mg, 1.27 mmol) in dry THF (5 mL) under argon, 60% NaH in mineral oil (64 mg, 1.59 mmol, 1.25 eq) was added in a portion-wise manner. After stirring for thirty minutes, MeI (99 μL, 1.59 mmol, 1.25 eq) was added dropwise, and the reaction was stirred for 2 days at room temperature. The resulting mixture was diluted with brine and extracted three times with Et2O. The combined organic phases were dried with Na2SO4, concentrated, and purified by column chromatography using 20:80:EtOAc:Hexane to give a yellow-white solid (228 mg, 62%): mp 125–126° C. 1HNMR (CDCl3, δ TMS): 0.86 (t, 3H), 1.37 (t, 3H), 1.94 (m, 2H), 2.15 (m, 2H), 2.78 (t, 2H), 2.85 (q, 2H) 3.37 (s, 3H), 3.52 (m, 2H), 4.00 (m, 2H), 6.99–7.38 (m, 3H, Ar—H), 8.43 (br, 1H, NH). MS−: m/z 286 ([M−H]−). Anal. (C18H25NO2): C, H, N.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Fc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1

Procedure:
The title compound (0.003 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 4-fluorobenzyl chloride (0.5 mL) in place of benzyl chloride. MS (ESI): exact mass calculated for C20H19ClFN3, 355.13; found, m/z 356.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.40-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.08-7.04 (m, 2H), 6.98-6.94 (m, 2H), 5.26 (s, 2H), 2.89-2.86 (m, 4H), 2.80-2.78 (m, 2H), 2.73-2.70 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].Cl[CH2:12][C:13]([CH3:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH2:12][C:13](=[O:14])[CH3:15]
Reactant: Oc1c(Br)cc(Br)cc1Br
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)COc1c(Br)cc(Br)cc1Br
Temperature: 27 °C
Yield: 96.5 %

Procedure:
A mixture of 5 g 2,4,6-tribromophenol (15 mmol), 1.4 g 1-chloroacetone (15 mmol), 4.16 g anhydrous potassium carbonate (30 mmol) and 20 ml DMF is stirred at 27° C. Completion of the reaction is confirmed by TLC. The reaction mass is diluted with water and extracted with ethylacetate The organic layer is washed with water and brine, dried over anhydrous sodium sulphate and concentrated to obtain 5.6 g 1-(2,4,6-tribromo-phenoxy)-propan-2-one (97%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:35])=[O:34]
Reactant: O=C(N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1coc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (500 mg, 1.16 mmol) (obtained as described in Reference Example 77(2)) in methylene chloride (25 ml) were added methanesulfonyl chloride (269 μl, 3.48 mmol) and triethylamine (488 μl, 3.48 mmol) in an ice bath and the mixture was stirred for 10 minutes and then at room temperature for 3 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (96:4) as the eluant to afford 3-methanesulfonyloxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (546 mg, yield 92%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:8](Br)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O1CCCC1>[CH3:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCC[Mg]Br
Reactant: CCCCCCCC/C=C\CCCCCCCCBr
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCCCCCCC
Yield: 99 %

Procedure:
To a stirred solution of 1.15 moles of amylmagnesium bromide in 335 ml. anhydrous tetrahydrofuran at -8° is added 0.028 moles of lithium chlorocyanocuprate in tetrahydrofuran, prepared in Example 1 above. Dropwise addition of 1.00 moles of Z-9-octadecenyl bromide is carried out with cooling to maintain the temperature at from about -6° to +5°. The reaction mixture is maintained at -5° to +5° for 1 hour. Magnesium bromide is precipitated by the addition of hexane and a minor amount of water. The slurry of granular solid is filtered and washed with hexane. Evaporation of solvent from the filtrate gives a clear amber oil of Z-9-tricosene in 99% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].Br([O-])(=O)=[O:42].[Na+]>CCOC(C)=O.O.O.[Ru]=O>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8](=[O:42])[CH2:9][CH2:10][CH2:11][C@H:12]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:13][O:14][Si:15]([C:28]([CH3:30])([CH3:31])[CH3:29])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: O=[Ru]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(=O)CCC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a stirred solution of the material from Step 2 (339.5 g, 595 mmol) in EtOAc (1000 mL) and H2O (1400 mL) at room temperature were added sodium bromate (250 g, 1657 mmol) and ruthenium oxide hydrate (3 g, 19.86 mmol). The reaction mixture was stirred at room temperature overnight, 50% of conversion. The mixture was then heated at 55° C. overnight. Additional sodium bromate (100 g) was added and the resulting mixture was heated at 40° C. for 12 hours. Upon cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was extracted with EtOAc (2×). The combined organics were then washed with aqueous sodium bisulfite and brine, and dried over MgSO4. The filtrate was treated with charcoal (Darco® G-60, Norit Americas Inc., Marshall, Tex.) and filtered through a pad of silica gel. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using EtOAc-hexanes to yield 128 g of the title compound as a colorless viscous oil. 1H NMR (CHCl3-d): δ 7.67-7.62 (m, 4H), 7.58-7.52 (b, 1H), 7.42-7.35 (m, 6H), 4.72-4.65 (b, 1H), 3.70-3.62 (m, 2H), 3.58-3.52 (m, 1H), 2.76-2.62 (m, 2H), 1.75-1.55 (m, 2H), 1.48 (s, 9H), 1.42 (s, 9H), 1.32-1.23 (m, 2H), 1.05 (s, 9H).