Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CC1CN(Cc2ccccc2)CCC1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC1CNCCC1O

Procedure:
A mixture of 1-benzyl-4-hydroxy-3-isobutylpiperidine (0.63 g, 2.5 mmole) and 20% palladium hydroxide (0.1 g) in methanol (20 ml) was stirred in hydrogen atmosphere (1 atm.) for 48 hr at 35° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 4-hydroxy-3-isobutylpiperidine as oil. Yield 0.35 g (91%), C9H19NO, m/z 158 (M+1).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].[ClH:8].[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18](=[NH:21])OC.Cl>CO.C(OCC)C.C(O)C>[ClH:8].[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18]1[NH:21][CH:3]=[CH:4][N:5]=1
Reactant: COC(=N)c1cc2ccccc2o1
Reactant: COC(CN)OC
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: CO
Product: c1ccc2oc(-c3ncc[nH]3)cc2c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of aminoacetaldehyde dimethylacetal (7.3 g) and methyl benzofuran-2carboximidate hydrochloride (13.4 g) in methanol (135 ml) was stirred at 60° C. for 16 hours. The mixture was then evaporated to dryness. Hydrochloric acid (750 ml, 2M) was added and the resulting mixture was stirred at 60° C. for 16 hours. After cooling, the solution was washed with dichloromethane. The aqueous layer was basified with sodium hydroxide and the free base was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried. Evaporation of the solvent gave a solid residue which was dissolved in diethyl ether/ethanol. Ethereal HCl was added to solution and the precipitated salt was collected by filtration (12.5 g, 90%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:9]1[CH:8]=[CH:7][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: OCCCCBr
Reactant: Oc1ccc2ccccc2c1
Product: BrCCCCOc1ccc2ccccc2c1

Procedure:
This example was prepared by substituting 3-bromopropanol with 4-bromobutanol and substituting 1-naphthol with 2-naphthol in EXAMPLE 31A.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.Cl[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:20]=[C:19]([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[C:30]2[S:38][CH3:39])[N:18]=1.CC(O)=O>C1COCC1.O>[CH3:39][S:38][C:30]1[N:29]([C:19]2[N:20]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:22]=[C:17]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:18]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=1
Reactant: Nc1cccnc1
Reactant: CSc1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CSc1nc2ccccc2n1-c1nc(Nc2cccnc2)nc(N2CCOCC2)n1
Reaction time: 0.08 h
Yield: 78.5 %

Procedure:
A solution of 3-aminopyridine (2 g, 21 mmol) in 100 mL THF was treated with 10.6 mL (21 mmol) 2 M LDA in THF to give a suspension which was treated with 1.81 g (5 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(methylsulfanyl)-1H-benzimidazole at room temperature. After 5 min, the mixture was neutralized with HOAc and diluted with water to give 1.65 g (78%) of 4-[2-(methylsulfanyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridinyl)-1,3,5-triazin-2-amine: mp (CHCl3/EtOH) 240-241° C.; 1H NMR (CDCl3) δ 8.85 (br s, 1H), 8.39 (d, J=4.0 Hz, 1H), 8.34 (d, J=7.5 Hz, 1H), 8.02 (d, J=7.3 Hz, 1H), 7.66 (dd, J=7.9, 0.5 Hz, 1H), 7.32 (dd, J=8.5, 4.9 Hz, 1H), 7.28 (dt, J=7.3, 1.1 Hz, 1H), 7.22 (t, J=7.4 Hz, 1H), 7.15 (br s, exchangeable with D2O, 1H), 4.05 (m, 2H), 3.90 (m, 2H), 3.81 (m, 4H), 2.73 (s, 3H); Anal. Calcd. for C20H20N8OS: C, 57.1; H, 4.8; N, 26.65. Found: C, 57.0; H, 4.9; N, 27.0%.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].[NH2:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH3:13].C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH3:13])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])([OH:5])=[O:4]
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCC(=O)O)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Yield: 74.8 %

Procedure:
2-Oxoglutaric acid (1.46 g) and L-alanyl-L-proline (0.37 g) were treated with sodium cyanoborohydride (0.38 g) as described above. Crude N-(1,3-dicarboxypropyl)-L-alanyl-L-proline (0.47 g) was obtained, m.p. 140°-160°. The mass spectrum of silylated material showed an ion at 517 m/e equivalent to the molecular ion for the trisilylated derivative minus methyl (532-15). The nmr spectrum was consistent with structure. Methyl resonances were centered at 1.4 ppm.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:36])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:33]([C:29]1[CH:28]=[C:27]([C:25]2[CH2:24][C:23](=[O:36])[NH:22][C:9]3[CH:10]=[C:11]([C:14]#[C:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:32]=[CH:31][CH:30]=1)([O-:35])=[O:34]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc([N+](=O)[O-])c2)=Nc2ccc(C#Cc3ccccc3)cc2N1
Yield: 85.3 %

Procedure:
Prepared from {2-[3-(3-nitro-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester (Example K31) (970 mg, 1.94 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (631 mg).
Reaction SMILES: COC1[C@@H](C(C)C)N=[C:6]([O:26]C)[C@H:7]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@H:13]2[C:18]([O:19][CH3:20])=N[C@H](C(C)C)C(OC)=[N:14]2)[N:8]=1.Cl.CC#N.[CH3:35][OH:36].[O:37]1CCOCC1>O>[CH3:35][O:36][C:6](=[O:26])[C@@H:7]([NH2:8])[CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@H:13]([NH2:14])[C:18]([O:19][CH3:20])=[O:37]
Reactant: CO
Reactant: C1COCCO1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C/C=C\C[C@@H]1N=C(OC)[C@@H](C(C)C)N=C1OC
Agent: Cl
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@@H](N)C/C=C\C[C@H](N)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,4-Bis((2R,5S)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-pyrazinyl)-(Z)-but-2-ene (0.58 g, 1.23 mmol) was dissolved in dioxane (8 ml), and 0.25M HCl (8 ml, 2.5 mmol) was added and stirred overnight at ambient temperature. TLC(MeCN:MeOH:H2O/4:1:1). The solution was extracted with diethyl ether, and the aqueous phase was evaporated. The residue was dissolved in a small amount of water, and aqueous ammonia solution was added until a pH of 9 was reached. The aqueous phase was extracted twice with diethyl ether, and the organic phase was dried over MgSO4 and evaporated.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:15]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1cccnc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 33.9 %

Procedure:
tert-butyl piperazine-1-carboxylate (3.0 g, 16.11 mmol) and 2-chloro-3-trifluoromethyl pyridine (2.93 g, 16.11 mmol) charged to a microwave vial was added with diisopropylethylamine (7.05 mL, 40.28 mmol) and DMF (1.0 mL). The reaction mixture was subject to microwave irradiation at 160° C. for 30 minutes. The reaction mixture was partitioned between EtOAc and water, organic layer washed with brine and dried over Na2SO4. The crude product obtained by solvent evaporation was purified via flash column chromatography. 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was obtained in 33.9% yield (1.81 g) as light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2.Cl.[CH:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.O>[CH:17]1([C:20]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]3)=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(O)C1CC1
Reactant: COC(=O)c1cnc2ccc(N)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cnc2ccc(NC(=O)C3CC3)cc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of methyl 6-aminoquinoline-3-carboxylate.2 HCl (Int-3, 0.125 g, 0.524 mmol) and cyclopropanecarboxylic acid (45.7 μL, 0.576 mmol) in pyridine (1.98 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.301 g, 1.57 mmol). The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate three times. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (hexanes to 40/60 hexanes/ethyl acetate gradient) to afford Int-4 (0.071 g, 50%). LC-MS: (FA) ES+ 271; 1H NMR (400 MHz, d6-DMSO) δ ppm 10.65 (s, 1H), 9.17 (d, J=2.1 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H), 8.05 (d, J=9.1 Hz, 1H), 7.98 (dd, J=9.1, 2.3 Hz, 1H), 3.93 (s, 3H), 1.86 (tt, J=7.1, 7.1, 5.3, 5.3 Hz, 1H), 0.90-0.80 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:23]([N+:24]([O-])=O)=[CH:22][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C@H:10]2[O:20][CH3:21])=[O:7])=[C:4]([O:27][CH3:28])[CH:3]=1.S1C=CC=C1.[H][H]>CO.[Pt]>[NH2:24][C:23]1[C:2]([Cl:1])=[CH:3][C:4]([O:27][CH3:28])=[C:5]([CH:22]=1)[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C@H:10]1[O:20][CH3:21])=[O:7]
Reactant: CCOC(=O)N1CC[C@H](NC(=O)c2cc([N+](=O)[O-])c(Cl)cc2OC)[C@H](OC)C1
Reactant: [H][H]
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Product: CCOC(=O)N1CC[C@H](NC(=O)c2cc(N)c(Cl)cc2OC)[C@H](OC)C1
Yield: 94 %

Procedure:
A mixture of 90.5 parts of ethyl cis-4-[(4-chloro-2-methoxy-5-nitrobenzoyl)amino]-3-methoxy-1-piperidinecarboxylate, 3 parts of a solution of thiophene in methanol 4% and 400 parts of methanol was hydrogenated at normal pressure and at 50° C. with 5 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 80 parts (94%) of ethyl cis-4-[(5-amino-4-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinecarboxylate: mp. 142.5° C. (interm. 14).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]=[CH:5][C:4]1=[O:57])[CH3:2].C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.7 %

Procedure:
A solution of 17-ethyl-1-hydroxy-12-[2'-(4"-azido-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone (55 mg, Example 3), tetrakistriphenylphosphine palladium (10 mg), and acetic acid (10 ml) in 3 ml of dry toluene was stirred for 5 min at room temperature under nitrogen atmosphere. To this yellow solution was added tributyltin hydride (40 ml) and stirred an additional 45 min. at room temperature. The brown colored reaction mixture was subjected to column chromatography on silica gel (eluted first with hexane and then with 50% ethyl acetate/hexane) to give 50 mg of the title compound. Mass and 1H NMR data were consistent with the structure.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].[CH3:18][C:19](=[N:23]O)[C:20](=O)[CH3:21].[ClH:25].C(OCC)(=O)C>C(OCC)C>[Cl:25][CH2:18][C:19]1[N:23]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([O:13][S:14]([CH3:17])(=[O:15])=[O:16])=[C:7]([CH:12]=2)[C:8]([O:10][CH3:11])=[O:9])[O:2][C:20]=1[CH3:21]
Reactant: Cl
Reactant: COC(=O)c1cc(C=O)ccc1OS(C)(=O)=O
Reactant: CC(=O)C(C)=NO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1cc(-c2nc(CCl)c(C)o2)ccc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 51 %

Procedure:
A mixture of methyl 5-formyl-2-methanesulfonyloxybenzoate (31.20 g), 2,3-butanedione-2-oxime (12.23 g) and 4N hydrogenchloride-ethyl acetate solution (300 mL) was stirred at room temperature for 2 days. After concentration of the reaction mixture, diethyl ether was added to the residue and the precipitated crystals were collected by filtration. A mixture of the obtained crystal, tetrahydrofuran (300 mL) and thionyl chloride (21.65 g) was heated under reflux for 1 hr. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 5-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)-2-methanesulfonyloxybenzoate as colorless crystals (22.0 g, yield 51%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 160-161° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].Cl[O-].[Na+].[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]([OH:38])[CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH2:35][C:36]#[CH:37])[CH2:31][CH2:30]3)=[CH:21][C:19]=2[N:20]=1.C(N(CC)CC)C>ClCCl.CO>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[CH:37]=[C:36]([CH2:35][N:32]2[CH2:33][CH2:34][N:29]([CH2:28][C@H:27]([OH:38])[CH2:26][O:25][C:22]3[CH:23]=[CH:24][C:18]4[S:17][C:16]([CH3:15])=[N:20][C:19]=4[CH:21]=3)[CH2:30][CH2:31]2)[O:6][N:5]=1
Reactant: ON=Cc1cccc(Cl)c1Cl
Reactant: C#CCN1CCN(C[C@H](O)COc2ccc3sc(C)nc3c2)CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1nc2cc(OC[C@@H](O)CN3CCN(Cc4cc(-c5cccc(Cl)c5Cl)no4)CC3)ccc2s1
Reaction time: 0.07 h
Yield: 4.1 %

Procedure:
To a solution of 2,3 dichlorobenzaldehyde oxime (136 mg, 0.725 mmol) in 1 ml of dichloromethane was added aqueous sodium hypochlorite solution (>4%, 1.35 ml, 0.725 mmol). The reaction was sealed in a reaction vessel with a stirbar. The vessel was subjected to microwave under the following conditions: temperature=60° C., time=240(s), high absorbance, fixed hold time=on, pre-stir=10(s). After 4 minutes (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-(4-prop-2-ynylpiperazinyl)propan-2-ol (50 mg, 0.145 mmol) in 1 ml of dichloromethane was added, followed by triethylamine (0.022 ml, 0.145 mmol). The reaction vessel was again subjected to microwave under the following conditions: temperature=110° C., time=240(s), high absorbance, fixed hold time=on, pre-stir=10(s). After 4 minutes, thin layer chromatography (10:1 dichloromethane:methanol) showed consumption of starting material and product formation. The solution was evaporated under reduced pressure and purified by preparative thin layer chromatography (10:1 dichloromethane:methanol) followed by HPLC to yield (2S)-3-(4-{[3-(2,3-dichlorophenyl)isoxazol-5-yl]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol (20) (3.2 mg, M+1=533.21)
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][O:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)CO.[OH-].[Na+:14]>O>[CH2:1]([O-:8])[CH2:2][O:3][CH2:4][CH2:5][CH2:6][CH3:7].[Na+:14]
Reactant: CCCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CCCCOCC[O-]
Temperature: 120 °C

Procedure:
Into a 1 liter three-necked flask, equipped as described in Example 1, 590 g of 3-oxaheptan-1-ol (i.e., the butyl monoether of ethylene glycol) are introduced. 40 g of sodium hydroxide in pellet form are added and the mixture is heated to 120° C. Sodium 3-oxaheptan-1-olate and water are formed, with the latter being removed by distillation.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]1=[O:18].CO.N1C=CC=CC=1.[I:27]Cl>C(Cl)Cl>[I:27][C:10]1[CH:11]=[CH:12][C:6]2[NH:5][CH:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3](=[O:18])[N:2]([CH3:1])[CH2:8][C:7]=2[CH:9]=1
Reactant: COC(=O)CC1Nc2ccccc2CN(C)C1=O
Reactant: ClI
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC1Nc2ccc(I)cc2CN(C)C1=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
Methyl 2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate (100 g, 0.4 moles) was added to CH2Cl2 (500 ml) plus MeOH (500 ml) and heated at 40° C. for 0.5 hr. The solution was cooled to 26° C. and pyridine (64 g, 0.8 mole) added. Iodine monochloride (71.3 g, 0.44 mole) dissolved in CH2Cl2 (500 ml) was added dropwise over 30 minutes and the reaction stirred for a further 1.0 hr. The product was filtered off, washed with 60/80 petrol and dried in vacuo to yield the title compound (113 g, 75%).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[C:7]=1[CH:8]=[O:9].O>ClCCl>[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:7]=1[CH:8]=[O:9]
Reactant: COc1cccc(F)c1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=Cc1c(O)cccc1F
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A solution of boron tribromide in dichloromethane (1M; 20.15 ml) was added dropwise to a stirring solution of 2-fluoro-6-methoxybenzaldehyde (4.66 g, prepared as described above) in dichloromethane (40 ml) at -78° C. The mixture was allowed to warm to ambient temperature then water (150 ml) was added and the mixture extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (100 ml) then brine (100 ml) and the solvent evaporated. Distillation of the residue at reduced pressure gave 2-fluoro-6-hydroxybenzaldehyde (2.0 g), contaminated with 7% of the starting methoxy compound, as an oil b.p. 60° C. at 4.66 mbar, which was used without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.Cl[P:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24].Cl[Sn:30]([CH2:39][CH2:40][CH2:41][CH3:42])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34]>CCOCC>[CH2:39]([Sn:30]([C:2]1[CH:3]([P:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[C:4]2[C:9]([CH:1]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:40][CH2:41][CH3:42]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C1=Cc2ccccc2C1
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)C1=Cc2ccccc2C1P(C(C)C)C(C)C
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 102.7 %

Procedure:
100 ml of ether were placed in a round-bottomed flask containing 3.8 g (0.033 moles) of indene and the solution was cooled to −20° C. 14.4 ml of a 2.3 molar solution of butyllithium in hexane (0.033 moles) were added over 5 minutes to form a yellow solution. After removal of the cooling bath, the solution was heated to room temperature and subsequently stirred for 1.5 h. The reaction mixture was then cooled to 0° C. and 5.0 g of chlorodiisopropylphosphine (0.033 moles) were added to form a precipitate. After removal of the cooling bath, the solution was heated to room temperature and stirred for 1 h. The solution was then cooled to −20° C. and 14.4 ml of a 2.3 molar solution of butyllithium in hexane (0.033 moles) were added dropwise. When the addition was complete, the cooling bath was removed and the solution was heated slowly to room temperature and stirred for 1.5 h. After cooling of the suspension to 0° C., 10.1 g of chlorotributyltin (0.031 moles) were added dropwise. The suspension formed was heated to room temperature and stirred for 1.5 h. The ether was removed under vacuum, the crude product was dissolved in hexane again, the solution was filtered and the filtrate was concentrated to dryness under vacuum to leave 16.6 g of compound 8 (yield: 97%) in the form of a heavy yellow oil. Two isomers were obtained in proportions of 1.5:1. The main isomer was identified as follows: 1H NMR (400 MHz, CD2Cl2): δ=7.71 (d, J=7.2 Hz, 1H); 7.41 (d, J=7.3 Hz, 1H); 7.13 (m, 2H); 6.96 (m, 1H); 4.28 (s with Sn satellites, 1H); 2.21 (m, 1H); 1.54 (m, 1H); 1.45-0.65 (m, 39H); 31P NMR (161.9 MHz, CD2Cl2): δ=−11.3 ppm. The secondary isomer was identified as follows: 1H NMR (400 MHz, CD2Cl2): δ=7.6 (d, J=7.4 Hz, 1H); 7.46 (d, J=7.2 Hz, 1H); 7.26 (t, J=7.5 Hz, 1H); 7.1 (m, 1H); 6.71 (m, 1H); 3.48 (m, 1H); 2.21 (m, 1H); 1.54 (m, 1H); 1.45-0.65 (m, 39H); 31P NMR (161.9 MHz, CD2Cl2): d=−1.5 ppm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](O)=O.S(Cl)(Cl)=O.[ClH:17].[CH3:18][NH:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>ClCCl.N1C=CC=CC=1>[CH3:18][N:19]([C:2](=[O:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Cl:17])[OH:20]
Reactant: Cl
Reactant: CNO
Reactant: O=C(O)CCCCCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(O)C(=O)CCCCCCCCCl

Procedure:
A mixture of 1.02 g (5.85 mmol) of 9-hydroxynonanoic acid (IV4), 1 ml of thionyl chloride, and a drop portion of pyridine was heated for 3 hours on a warm bath at 70° C. and the remainder thionyl chloride was evaporated under reduced pressure. A solution of the resulting residue in 20 ml of dichloromethane was treated with 20 ml of an aqueous solution of 530 mg (6.35 mmol) of methylhydroxylamine hydrochloride and 900 mg (6.5 mmol) of potassium carbonate according to the procedure shown in Example 10 to give N-methyl-9-chlorononanohydroxamic acid (V8), which was chromatographed on silica gel eluted with ether to give 534 mg of the pure compound (V8) as a pale yellow oil in 41.1% yield. A solution of 534 g (2.4 mmol) of the compound (V8) and 580 mg (2.4 mmol) of 2,6-di-tert-butyl-4-mercaptophenol in 10 ml of ethanol was treated in the presence of 414 mg (3 mmol) of potassium carbonate and 20 mg of N-tetra-n-butylammonium iodide according to the procedure shown in Example 9. The product was chromatographed on silica gel and eluted with a mixture of dichloromethane-ethyl acetate (1:1) to give 260 mg of the aimed compound (I12) as a pale yellow oil in 25.5% yield.