Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[S:22][C:21]4[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:20]=4[C:19]=3[CH3:28])(=[O:17])=[O:16])=[C:10]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:9]=2)[S:6][CH:7]=1.[I-].[Na+]>CC(C)=O>[F:27][C:25]1[CH:24]=[CH:23][C:21]2[S:22][C:18]([S:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([C:5]4[S:6][CH:7]=[C:3]([CH3:2])[N:4]=4)=[CH:9][C:10]=3[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:16])=[O:17])=[C:19]([CH3:28])[C:20]=2[CH:26]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(-c3nc(CCl)cs3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1csc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.5 %

Procedure:
Into 10 mL of acetone was dissolved 64 mg of Compound 64, and 180 mg of sodium iodide was added, followed by 24 hours of heating under refluxing. Further, 180 mg of sodium iodide was added and the mixture was heated under refluxing for 19 hours. The solvent was removed by evaporation under reduced pressure and the residue was dissolved into ethyl acetate. The solution was washed with water, 5% aqueous sodium thiosulfate solution, water and saturated brine, successively, and then dried over anhydrous sodium sulfate. After the solvent was removed by evaporation under reduced pressure, the resulting 5-fluoro-N-[4-(4-iodomethylthiazol-2-yl)-2-methanesulfonylphenyl]-3-methylbenzo[b]thiophene-2-sulfonamide was dissolved into a mixed solution of 5 mL of toluene and 0.5 mL of DMSO, and 45 μL of tributyltin hydride and 13 μL of 1.06 mol/L hexane solution of triethylboron were added, followed by 6 hours of stirring at room temperature. Further, 24 μl of tributyltin hydride was added and the mixture was stirred at room temperature for 3 hours. Then, the reaction was terminated by adding saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, successively, and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane to hexane/ethyl acetate=3/1) to obtain 29 mg of the title compound as colorless powder.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:30][C@@:28]3([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]3[OH:31])[C@H:23]3[C@H:14]2[C:15]2[CH:16]=[CH:17][C:18]([OH:32])=[CH:19][C:20]=2[CH2:21][CH2:22]3)=[CH:9][CH:8]=1.[C:33]([O-])(=[S:35])[CH3:34].[K+]>>[C:33]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:30][C@@:28]3([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]3[OH:31])[C@H:23]3[C@H:14]2[C:15]2[CH:16]=[CH:17][C:18]([OH:32])=[CH:19][C:20]=2[CH2:21][CH2:22]3)=[CH:9][CH:8]=1)(=[S:35])[CH3:34]
Reactant: CC([O-])=S
Reactant: C[C@]12C[C@H](c3ccc(OCCCCI)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: [K+]
Product: CC(=S)CCCCOc1ccc([C@H]2C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]3CCc4cc(O)ccc4[C@H]32)cc1
Yield: 82.2 %

Procedure:
The operation is carried out as in Stage E of Example 8 starting with 1.18 g of the product obtained in Stage D and 460 mg of potassium thioacetate. 850 mg of expected product is obtained. M.p. # 90° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Br.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC(C)=O>[Br:9][C:10]1[CH:11]=[C:12]([CH2:13][O:8][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: BrCc1cccc(Br)c1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1cccc(COc2cccc(Br)c2)c1
Temperature: 25 °C

Procedure:
A mixture of 3-bromophenol (13.8 g, 80 mmol), 3-bromobenzyl bromide (10 g, 40 mmol), K2CO3 (16.6 g. 120 mmol) and NaI (300 mg, 2 mmol) in acetone (100 mL) was heated to reflux for 12 hours. The reaction mixture was cooled to rt, concentrated in vacuo and partitioned between Et2O (300 mL) and water (300 mL). The organic phase was washed with aqueous NaOH (1 M, 300 mL), dried (Na2SO4), filtered and concentrated in vacuo to give 3-[(m-bromophenyl)methoxy]bromobenzene as a clear oil. MS (APCI) m/z 339 (M+−3, 50%), 341 (M+−1, 100%), 343 (M++3, 50%), 13C NMR (50 MHz, CDCl3); δ 68.9, 113.4, 117.9, 122.5, 122.6, 124.1, 125.6, 129.9, 130.0, 130.4, 130.9, 138.4, 158.9.
Reaction SMILES: I.[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5](SC)[NH:4]1.[NH2:15][CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1>C(#N)C.C(O)(C(F)(F)F)=O>[CH:16]1([NH:15][C:5]2[NH:4][CH:3]([CH3:2])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: NC1CCc2ccccc21
Reactant: CSC1=Nc2ccccc2C(C)N1
Agent: I
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC1NC(NC2CCc3ccccc32)=Nc2ccccc21
Temperature: 85 °C

Procedure:
4-Methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (31 mg, 0.10 mmol) and (+/−)-1-aminoindane (17 mg, 0.12 mmol) were suspended in acetonitrile (1 ml) and heated in a screw-capped vial to 85° C. (12 h). The product was isolated from the reaction mixture by preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 7.0 min, λ=230 nm, flow rate 40 ml/min) to give the title compound (MS: m/e=264.2 [M+H+]).
Reaction SMILES: C1C2C(COC(N[C@H:19]([C:27]([OH:29])=[O:28])[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])([CH3:22])[CH3:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.CN(C)C=[O:39]>>[OH:39][C@@H:19]([C:20]([CH3:22])([S:23]([CH3:26])(=[O:25])=[O:24])[CH3:21])[C:27]([OH:29])=[O:28]
Reactant: CC(C)([C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)S(C)(=O)=O
Reactant: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)([C@H](O)C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of the product from Example 156B (0.35 g, 0.838 mmol) in N,N-dimethylformamide (3.0 mL) was added piperidine (0.17 mL, 1.72 mmol), and this mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between dichloromethane and water. The isolated organic layer was washed with brine and dried over MgSO4, filtered and evaporated. The residue dissolved in water (1.0 mL) and concentrated sulfuric acid (0.10 mL) was added at room temperature, followed by heating to 50° C. A solution of sodium nitrite (0.25 g) in water (0.60 mL) was added dropwise at 50° C. and the reaction was stirred for 1 hour. The reaction was extracted with ethyl acetate and washed with water and brine. The organic was dried over MgSO4, filtered and evaporated to give the crude product (0.041 g, 25% yield), which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[C:15]([OH:16])=[CH:14][C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=1.[CH3:21][N:22]1CCCC1=O>>[C:21]([C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[C:15]([OH:16])=[CH:14][C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=1)#[N:22]
Reactant: Oc1cc2c(cc1CC=Cc1ccccc1Br)OCC2
Reactant: CN1CCCC1=O
Product: N#Cc1ccccc1C=CCc1cc2c(cc1O)CCO2
Temperature: 25 °C

Procedure:
6-(o-Bromocinnamyl)-2,3-dihydro-5-hydroxy-benzofuran (1.49 g; 4.5 mM) and cuprous cyanide (1.37 g; 15.3 mM) were suspended in 18 ml of anhydrous N-methyl-2-pyrollidinone. Nitrogen was bubbled through this suspension for approximately 15 minutes and the reaction mixture was then heated to 175° under nitrogen for 2 hours. After cooling to ambient temperature the reaction was poured into 60 ml of water containing 60 ml of concentrated ammonium hydroxide. This emulsion was extracted three times with ether, dried over magnesium sulfate and stripped to a brown oil. Flash chromatography of this material on a 30 mm by 51/2" column of silica gel eluted with 500 ml of 35% ethyl acetate in hexane gave a solid which was recrystallized from ethyl acetate/hexane producing 0.95 g (76%) of white crystals identified as 6-(o-cyanocinnamyl)-2,3-dihydro-5-hydroxy-benzofuran.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[I-].ClC1C=[CH:28][CH:27]=[CH:26][N+]=1C.C(O)(C)C.C(N(CC)CC)C>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([O:16][CH:27]([CH3:28])[CH3:26])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Reactant: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
One g of 2-[2-(4-fluorophenyl)-5-(3-thienyl)-4-oxazolyl]acetic acid, 0.93 g of 2-chloro-1-methyl-pyridinium iodide and 0.2 g of isopropanol are dissolved in 40 ml of tetrahydrofuran, and 0.66 g of triethylamine is added dropwise thereto. The mixture is stirred at room temperature for 18 hours. Then, water is added to the reaction mixture, and said mixture is condensed under reduced pressure to remove tetrahydrofuran. The residue is extracted with ethyl acetate, and the extract is washed with an aqueous 20% citric acid solution, an aqueous sodium bicarbonate solution and water, successively. Said extract is dried and then condensed to remove solvent, and the residue is recrystallized from ethanol. 0.85 g of isopropyl 2-[2-(4-fluorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate is thereby obtained.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:8]([OH:9])[C@@H:7]([OH:10])[CH2:6][O:5][CH:3]1[OH:4].Cl>>[F:1][C@@H:2]1[C@@H:8]([OH:9])[C@H:7]([CH2:6][OH:5])[O:10][CH:3]1[OH:4]
Reactant: OC1OC[C@H](O)[C@H](O)[C@H]1F
Agent: Cl
Product: OC[C@@H]1OC(O)[C@H](F)[C@H]1O

Procedure:
Treatment of unprotected 2-deoxy-2-fluoro-L-arabinopyranose with one equivalent of either sulfuric or hydrochloric acid at room temperature failed to give the desired furanoside. Only unreacted starting material was detected. Using nine equivalents of hydrochloric acid gave the desired product 2-deoxy-2-fluoro-L-arabinofuranose, which was contaminated with starting material (2:1 ratio). The best result, so far, was achieved by refluxing 2-deoxy-2-fluoro-L-arabinopyranose with 1 equivalent of sulfuric acid in dry methanol. After 6 hours all of the starting material had disappeared affording 2-deoxy-2-fluoro-L-arabinofuranose as an oil in 80% yield. 1H-, 13C- and 19F-NMR indicated a 3:1 α:β mixture of anomers, with some minor impurities. L-ribo- and L-arabinopyranoside as well as L-ribofuranoside are the possible side products. The D-isomer of 2-deoxy-2-fluoro-L-arabinofuranose was previously made by two different groups, but in less efficient ways (Wright, J. A.; Taylor, N. F.; Fox, J. J. J. Org. Chem 1969, 34, 2632. and Wysocki, R. J.; Siddiqui, M. A.; Barchi, J. J.; Driscoll, J. S.; Marquez, V. E. Synthesis 1991, 1005).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Zn](C)C.CN([C@@H](C1C2C(=CC=CC=2)C=CC=1)C1C2C(=CC=CC=2)C=CC=1O)[C@H](C1C=CC=CC=1)C.[Cl:45][C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[CH:48]=[O:49]>C1(C)C=CC=CC=1>[Cl:45][C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[C@@H:48]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:49]
Reactant: O=Cc1ccccc1Cl
Reactant: OB(O)c1ccccc1
Agent: C[C@@H](c1ccccc1)N(C)[C@@H](c1cccc2ccccc12)c1c(O)ccc2ccccc12
Agent: C[Zn]C
Solvent: Cc1ccccc1
Product: O[C@H](c1ccccc1)c1ccccc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
PhB(OH)2 (122 mg, 1.0 mmol) and ZnMe2 (2.0 M solution in toluene, 1.6 mL)) is charged to a 10 mL flask under a nitrogin atmosphere. This mixture is heated to 50° C. and stirred for 8 h with a magnetic stirrer. Then the mixture is cooled to 0° C. and the title compound of Example 1, 1-{(S)-[methyl-((S)-1-phenyl-ethyl)-amino]-naphthalen-1-yl-methyl}-naphthalen-2-ol (16.7 mg, 0.04 mmol) in toluene (0.5 mL) and DiMPEG (100 mg, 0.05 mmol) in toluene (0.5 mL) are added. After stirring for additional 15 min, the solution is cooled to −15° C. and 2-chlorobenzaldehyde (70 mg, 0.5 mmol) in toluene (1 mL) is added. After stirring 15 h at −15° C., the reaction is quenched with 1 N HCl (2 mL) and the mixture is extracted with EtOAc (5 mL), dried over anhydrous Na2SO4 and the solvent is removed in vacuo. The purification of the residue by flash chromatography (EtOAc/hexane, 1:10) gives (R)-(2-chlorophenyl)phenylmethanol in about 97.0% ee and about 86.6% yield (the ee value is determined by HPLC using a Chiralcel OB-H column).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:20][C:21]1([CH3:29])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]1)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:20][C:21]2([CH3:29])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]2)=[CH:4][N:3]=1
Reactant: CC1(COS(C)(=O)=O)COC(C)(C)OC1
Reactant: Oc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(COc2cnc(Cl)nc2)COC(C)(C)OC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 30.2 %

Procedure:
To a solution of 9.50 g (72.8 mmol) of 2-chloro-5-hydroxypyrimidine in 100 ml of N,N-dimethylformamide, 26.1 g (80.1 mmol) of cesium carbonate and 24.3 g (102 mmol) of 5-(methanesulfonyloxymethyl)-2,2,5-trimethyl-1,3-dioxane, which was synthesized by the method described in V. W. Gash, Journal of Organic Chemistry, 1972, Vol. 37, p. 2197-2201, were added, and the mixture was stirred at 90° C. for 24 hours. After completion of the reaction, the insoluble material was filtered off and washed with ethyl acetate, and then 0.5 N sodium hydroxide aqueous solution was added to the filtrate and separation was performed. The obtained aqueous layer was further extracted with ethyl acetate. The obtained organic layers were combined, washed with water and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Toluene was added to the obtained residue, and the precipitate was obtained by filtration and washed with toluene and n-heptane to provide 6.00 g of the title compound as a white solid (yield: 30%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[OH:23][CH2:24][CH:25]([N:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)[C:28]1=[O:45])[CH3:26]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[C:28](=[O:45])[N:27]([CH:25]([CH3:26])[CH2:24][OH:23])[CH2:35]4)[C:16]2=[CH:15][N:14]=1
Reactant: CC(CO)N1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(C(C)CO)C5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-(2-hydroxy-1-methylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=482.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2O.O=P(Cl)(Cl)[Cl:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[Cl:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1O
Product: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Temperature: 25 °C

Procedure:
20 g (74.3 mmol) of 6-bromo-3-nitro-quinolin-4-ol (Example 1b) in 150 ml (1.63 mol) of POCl3 are stirred for 45 min at 120° C. The mixture is cooled to RT and poured slowly into ice-water. The precipitate is filtered off, washed with ice-cold water, and dissolved in CH2Cl2. The organic phase is washed with cold brine, and the aqueous phase is discarded. After drying over MgSO4, the organic solvent is evaporated to dryness to provide the title compound. 1H NMR (CDCl3): δ 9.20/s (1H), 8.54/d (1H), 8.04/d (1H), 7.96/dd (1H); analytical HPLC: W=4.32 min (Grad 1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:4])=[O:3].[CH3:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C[Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:14][CH:15]1[CH2:20][CH2:19][N:18]([S:2]([C:5]2[CH:6]=[C:7]([CH2:8][OH:10])[CH:11]=[CH:12][CH:13]=2)(=[O:3])=[O:4])[CH2:17][CH2:16]1
Reactant: CC1CCNCC1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: CC1CCN(S(=O)(=O)c2cccc(CO)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11 g (50 mmol) of 3-chlorosulphonylbenzoic acid in suspension in dichloromethane (300 ml) is treated with 12.4 g (125 mmol) of 4-methylpiperidine and the reaction mixture is maintained under stirring at ambient temperature overnight. The resulting solution is washed successively with a 10% aqueous solution of citric acid and a saturated solution of sodium chloride, followed by drying (Na2SO4) and concentrating under reduced pressure in order to produce a colourless viscous residue. The latter is taken up in methanol and, whilst maintaining the temperature between 0° C. and 10° C., is titrated by trimethylsilyldiazomethane until a characteristic yellow coloration persists. The excess reagent is destroyed with a few drops of formic acid, and the reaction medium is concentrated under reduced pressure. The traces of acid and methanol are eliminated by two azeotropic evaporations under reduced pressure with toluene. The residue, taken up in tetrahydrofuran (300 ml), is treated with lithium borohydride (2N in THF, 30 ml). The reaction medium is taken to reflux for 2 hours then cooled down and hydrolyzed with a saturated solution of ammonium chloride. The resulting mixture is extracted with ethyl acetate then the organic phase is washed with a saturated solution of sodium chloride, followed by drying (Na2SO4) and concentrating under reduced pressure. The residue is purified on a silica column (eluent: 5% acetone in dichloromethane) in order to produce the expected benzyl alcohol in the form of a white solid.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccccc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccccc4)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and phenylisocyanate (0.12 g, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (10 mL) was added and the solids were isolated by filtration and washed with water (20 mL). The solids were triturated in EtOAc (10 mL) for 18 h, then isolated by filtration, washed with EtOAc (40 mL) and dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-phenyl-urea as a white solid (0.38 g, 97% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 6.94 min (96.31%); mp: 243-245° C.; 1H NMR (DMSO-d6) δ 1.88-2.12 (m, 1H, CHH), 2.27-2.47 (m, 1H, CHH), 2.59 (d, J=17.6 Hz, 1H, CHH), 2.77-3.06 (m, 1H, CHH), 4.31 (d, J=17.4 Hz, 1H, CHH), 4.37-4.56 (m, 3H, CHH, CH2), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CH), 6.73 (t, J=5.9 Hz, 1H, Ar), 6.82-6.98 (m, 1H, Ar), 7.22 (t, J=7.9 Hz, 2H, Ar), 7.33-7.49 (m, 3H, Ar), 7.52 (s, 1H, NH), 7.70 (d, J=7.7 Hz, 1H, Ar), 8.62 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.76, 47.12, 51.56, 117.72, 121.13, 121.86, 122.93, 126.88, 128.61, 130.29, 140.36, 142.39, 144.85, 155.22, 167.95, 170.99, 172.85; LCMS: MH=393; Anal Calcd for C21H20N4O4: C, 64.28; H, 5.14; N, 14.28. Found: C, 64.23; H, 4.94; N, 14.20.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]#[C:18][C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][CH:34]=1)[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]#[C:18][C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][CH:34]=1)[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCC#Cc1cccc(C(=O)OCc2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCOCCOCCOCCOCC#Cc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of benzyl 3-(1-azido-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate (23 g, 49.15 mmol, 1.00 equiv) in tetrahydrofuran (200 mL), water (20 mL), triphenylphosphine (25.7 g, 98.09 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane:methanol (100:1-50:1). This resulted in 15 g (69%) of benzyl 3-(1-amino-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate as pale-yellow oil.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][O:12][C:13](=[O:20])[CH2:14][C:15](=O)[CH2:16][O:17][CH3:18]>>[CH3:11][O:12][C:13]([C:14]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:2][O:1][C:15]=1[CH2:16][O:17][CH3:18])=[O:20]
Reactant: COCC(=O)CC(=O)OC
Reactant: O/N=C(\Cl)c1ccccc1
Product: COCc1onc(-c2ccccc2)c1C(=O)OC

Procedure:
As described for Example 36c, (E)- and/or (Z)-N-hydroxy-benzenecarboximidoyl chloride (14.04 g, 90 mmol) was converted, using 4-methoxy-3-oxo-butyric acid methyl ester instead of acteylacetone to the crude title compound (18.76 g) which was obtained as an off-white solid and used directly in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][C:7]([Cl:10])=[CH:8][CH:9]=1)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[N:19]/[NH:20][C:21](=[NH:23])[NH2:22])=[CH:14][CH:13]=1>C(O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15](/[CH:18]=[N:19]/[N:20]2[CH:2]=[C:3]([C:5]3[S:6][C:7]([Cl:10])=[CH:8][CH:9]=3)[N:22]=[C:21]2[NH2:23])=[CH:16][CH:17]=1
Reactant: O=C(CBr)c1ccc(Cl)s1
Reactant: N=C(N)N/N=C/c1ccc(Cl)cc1
Solvent: CCO
Product: Nc1nc(-c2ccc(Cl)s2)cn1/N=C/c1ccc(Cl)cc1
Reaction time: 10 h
Yield: 72 %

Procedure:
A solution of 2-bromo-1-(5-chloro-2-thienyl)-1-ethanone (1.07 g, 4.49 mmol), 2-[(E)-1-(4-chlorophenyl)methylidene]-1-hydrazinecarboximidamide (1.77 g, 8.98 mmol) was heated in ethanol (10 mL) for 2 h, then the mixture was left at room temperature for additional 10 h. The precipitate filtered, washed with hot water, and recrystallized from ethanol to give N1-[(E)-1-(4-chlorophenyl)methylidene]-4-(5-chloro-2-thienyl)-1H-1,2-imidazolediamine 2 (1.09 g, 72%) as a brown solid.