Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[CH3:7][S:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[O:22][N:21]=[C:20]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][NH2+:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH2:19]1)(=[O:10])=[O:9].C(N(CC)CC)C.O>ClCCl>[CH3:7][S:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[O:22][N:21]=[C:20]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:3](=[O:4])[CH2:2][Cl:1])[CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH2:19]1)(=[O:9])=[O:10]
Reactant: O=C(Cl)CCl
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CCN(C(=O)CCl)CC3)n2)=NO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
To a solution of chloroacetyl chloride (22 mg) was added, at 0° C., a solution of 4-[4-(5-{2-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidinium chloride (87 mg) and triethylamine (41 mg) in dichloromethane (1 ml). The reaction mixture was stirred at 0° C. for 15 minutes, and at room temperature for a further 18 hours. Then water was added thereto, and the aqueous phase was removed and extracted with dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave 2-(3-{2-[1-(chloroacetyl)piperidin-4-yl]-1,3-thiazol-4-yl}-4,5-dihydro-1,2-oxazol-5-yl)phenyl methanesulphonate (60 mg, 60%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][O:5][C:4]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:3]1=2.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23](Cl)=[O:24].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:4]3[O:5][CH2:6][C:2]([CH3:19])([CH3:1])[C:3]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:24]
Reactant: Cc1cc2c(cc1-c1ccc(N)nc1)C(C)(C)CO2
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c(cc1-c1ccc(NC(=O)c3c(F)cccc3F)nc1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of 5-(3,3,6-trimethyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (172) (25 mg, 0.1 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (25 μl, 2 eq) followed by addition of DIEA (87 μl). The resulting solution was stirred at r.t. for 2 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (200 μl) at r.t. for 1 h and before worked up with EA/brine. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(3,3,6-trimethyl(2,3-dihydrobenzo[b]furan-5-yl))(2-pyridyl)]carboxamide (173) (20.1 mg, yield: 51%, purity>95%) as white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C([O-])([O-])=O.[Na+].[Na+].[CH:12]1[CH:17]=[CH:16][C:15]([CH2:18][O:19][C:20](Cl)=[O:21])=[CH:14][CH:13]=1.C(Cl)Cl>C1COCC1.O>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:21])[O:19][CH2:18][C:15]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: NCCCO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NCCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a mixture of 3-aminopropan-1-ol (5.0 g, 67 mmol), Na2CO3 (8.8 g, 83 mmol) in THF (40 mL) and H2O (130 mL) at 0° C. was added Cbz-Cl (14.8 g, 87 mmol). The reaction mixture was stirred (RT, 1 h). Water (500 mL) and CH2Cl2 (500 mL) were added, and the layers were separated. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica chromatography (PE:EA, 5:1) to afford benzyl 3-hydroxypropylcarbamate as a white solid (12.6 g, 90.5%).
Reaction SMILES: [I-:1].[CH2:2]([C:6]1[CH:15]=[CH:14][C:13]2[N+:12]3[CH:16]=[C:17]4[CH:26]=[CH:25][C:24]5[CH:23]=[C:22](F)[CH:21]=[CH:20][C:19]=5[N:18]4[C:11]=3[CH:10]=[CH:9][C:8]=2[CH:7]=1)[CH2:3][CH2:4][CH3:5].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CN1CCCC1=O>CCOCC>[I-:1].[CH2:2]([C:6]1[CH:15]=[CH:14][C:13]2[N+:12]3[CH:16]=[C:17]4[CH:26]=[CH:25][C:24]5[CH:23]=[C:22]([N:28]6[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]6)[CH:21]=[CH:20][C:19]=5[N:18]4[C:11]=3[CH:10]=[CH:9][C:8]=2[CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: C1CCNCC1
Reactant: CCCCc1ccc2c(ccc3n4c(ccc5cc(F)ccc54)c[n+]23)c1
Agent: [I-]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCCCc1ccc2c(ccc3n4c(ccc5cc(N6CCCCC6)ccc54)c[n+]23)c1

Procedure:
A mixture of 4.7 g. of 3-butyl-10-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 5.0 ml. of piperidine and 50 ml. of N-methyl-2-pyrrolidinone is heated at reflux for 16 hours, then cooled and diluted with 400 ml. of ether. The resulting precipitate of 3-butyl-10-(1-piperidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration; m.p. 266°-267° C. (dec.), after crystallization from ethanol.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=O)[O:9]C(=O)[C:5]=2[CH:4]=1)[CH3:2].[N-:29]=[N+]=[N-].[Na+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:9])[NH:29][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)oc(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-2H-thieno[2,3-d][1,3]oxazine-1(4H)-yl)methyl]biphenyl-2-carbonitrile (3.5 g), sodium azide (0.88 g) and N,N-dimethylformamide (50 mL) was stirred at 50° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in toluene (30 mL), and the mixture was stirred at 110° C. for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.5 g, 46%).
Reaction SMILES: O=[C:2]1[C:15]2[C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2.O.[NH2:21][NH2:22]>CC(N(C)C)=O>[N:21]1[NH:22][C:16](=[O:18])[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=1[NH:9]3
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCCC3
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC1=C2CCCC1
Temperature: 130 °C
Reaction time: 12 h

Procedure:
To the solution of the crude methyl 9-oxo-5,6,7,8,9,10-hexahydroacridine-1-carboxylate in DMA (4 mL) was added hydrazine hydrate (4 mL) at room temperature, and the mixture was heated at 130° C. for 4.0 h. The reaction mixture was cooled to room temperature and stirred for another 12 hours. Then the mixture was filtered and recrystallized from MeOH (twice) to give the product (20 m g, 15%) as a yellow solid.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[F:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[F:17])[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)c(F)c1)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(F)c(F)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 53 %

Procedure:
3-[(3,4-Difluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 54-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to and gave the title compound as a white solid (53% yield); mp 146–147° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.74 (3H, s, OCH3), 4.16 (2H, s, NCH2), 4.79 (2H, s, NCH2), 7.06–7.19 (3H, m, aromatics). Anal. calcd for C14H14F2N2O4: C, 53.84; H, 4.51; N, 8.97. Found: C, 53.82; H, 4.41; N, 8.87.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.CI.[C:16](=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH3:16])[N:13]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(Br)c(-c2nnn[nH]2)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CI
Product: Cn1nnc(-c2cc(F)ccc2Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
A mixture of 5-(2-bromo-5-fluoro-phenyl)-1H-tetrazole (1.0 g, 4.12 mmol; Butt Park Ltd.), methyl iodide (1.12 g, 10 mmol) and potassium carbonate (1.5 g) in DMF (5 mL) was stirred at room temperature for 16 hrs, and the mixture concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, CH2Cl2) to provide 650 mg (2.53 mmol, yield 61%) of the title compound as a white powder (fast-moving 2-Me isomer): TLC, Rf 0.7 (CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 4.45 (3H, s) 7.03-7.11 (1H, m) 7.63 (1H, dd, J=8.9, 3.1 Hz) 7.69 (1H, dd, J=8.9, 5.5 Hz); 13C NMR (126 MHz, CDCl3) δ 39.86 (s) 116.28 (s) 118.66 (d, J=22 Hz) 118.76 (d, J=25 Hz) 130.13 (d, J=8.6 Hz) 135.73 (d, J=8.6 Hz) 161.74 (d, J=247.6 Hz) 163.53 (s); LC/MS m/z 257/259.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][C:21](=O)[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].Cl.[NH2:33][OH:34].O.CO>C1COCC1>[Cl:1][C:2]1[C:3]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:4]2[C:18]3[CH2:19][CH2:20]/[C:21](=[N:33]/[OH:34])/[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15]
Reactant: NO
Reactant: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCC(=O)C4)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CC/C(=N/O)C4)cc1

Procedure:
A mixture of the compound obtained in Example 33 (2.0 g), hydroxylamine hydrochloride (673 mg), water (5 ml), methanol (5 ml), and THF (40 ml) was heat under reflux for 2 hours and then evaporated under reduced pressure to remove the solvent. The residue was dissolved in methylene chloride and the resulting solution was washed with a saturated, aqueous solution of sodium hydrogen carbonate and water, dried (MgSO4), and then evaporated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel to obtain (Z)-1-{[3-chloro-7-(hydroxyimino)-4-(4-methoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.CCN(CC)CC.[CH3:35][N:36]([CH3:41])[S:37](Cl)(=[O:39])=[O:38].O>C(Cl)Cl>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:37]([N:36]([CH3:41])[CH3:35])(=[O:39])=[O:38])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)S(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Temperature: 0 °C

Procedure:
trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate A) (150 mg, 0.34 mmol) was dissolved in CH2Cl2 (1.5 ml) and the solution was cooled to 0° C. Et3N (139 mg, 1.37 mmol) and dimethylsulfamoylchloride (98 mg, 0.68 mmol) were added and the reaction mixture was stirred over night at room temperature. H2O was added and the product was extracted with CH2Cl2. The organic layer was dried (Na2SO4) and the solvent was evaporated. Purification by flash chromatography over silica gel (CH2Cl2/MeOH/25% NH3 aq 140:10:1) yielded the title compound as a white solid (89 mg, 60%), MS (ISP) m/z=436.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=C(C)S[C:13]=3[N:12]3C(C)=NN=[C:11]3[C:10]([CH3:25])([CH3:24])[N:9]=2)=[CH:4][CH:3]=1.N[C:27]1C=CC=C[C:28]=1C(C1C=CC(Cl)=CC=1)=O.NC1SC(C)=C(C)C=1C(C1C=CC(Cl)=CC=1)=[O:49]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[CH:19][CH:28]=[CH:27][C:13]=3[NH:12][C:11](=[O:49])[C:10]3([N:9]=2)[CH2:24][CH2:25]3)=[CH:6][CH:7]=1
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: Cc1sc(N)c(C(=O)c2ccc(Cl)cc2)c1C
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(C)(C)c1nnc(C)n1-2
Product: O=C1Nc2ccccc2C(c2ccc(Cl)cc2)=NC12CC2

Procedure:
A procedure analogous to that set forth in the synthesis of Compound 214 was followed, with the exception that (2-aminophenyl)(4-chlorophenyl)methanone was used as starting material instead of (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone. LRMS (M+H)+: 297 m/z.
Reaction SMILES: [CH2:1]([N:5]1[C@H:34]([CH2:35][O:36]CC2C=CC=CC=2)[C@@H:25]([O:26]CC2C=CC=CC=2)[C@H:16]([O:17]CC2C=CC=CC=2)[C@@H:7]([O:8]CC2C=CC=CC=2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].Cl.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>CO.O.[Pd]>[CH3:4][CH2:3][CH2:2][CH2:1][N:5]1[C@H:34]([CH2:35][OH:36])[C@@H:25]([OH:26])[C@H:16]([OH:17])[C@@H:7]([OH:8])[CH2:6]1
Reactant: CCCCN1C[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: O
Solvent: CO
Product: CCCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO
Reaction time: 4 h

Procedure:
A solution obtained by mixing N-butyl 2,3,4,6-tetra-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol of formula (III), obtained as in Example 2 (105.1 g, 0.17 mol) in methanol (500 ml) in the presence of 32% HCl (43.5 g). is treated with 16% Pd/C (10.2 g). The mixture is maintained under vigorous stirring under hydrogen atmosphere at 4 bars for about 4 hours, and then filtered through a perlite panel, and the solution obtained is concentrated at low pressure. The solid residue thus obtained is dissolved in water (100 ml), and the resulting acid solution is passed through a column on an ion-exchange resin activated in basic form (Amberlite IRA 900Cl). The fractions that tested positive to the ninhydrin assay were combined and concentrated at low pressure, obtaining 50 g of miglustat as an oily residue, having a chemical purity exceeding 98%, calculated by HPLC.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.Br[CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]1(=[O:26])[N:16]([CH2:15][CH2:14][CH2:13][O:11][C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=2)[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]12
Reactant: OCc1cc(O)cc(CO)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCOc1cc(CO)cc(CO)c1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
3,5-Bis-hydroxymethylphenol (Felder, D.; Gutierrez Nava, M.; del Pilar Carreon, M.; Eckert, J. F.; Luccisano, M.; Schall, C.; Masson, P.; Gallani, J. L.; Heinrich, B.; Guillon, D.; Nierengarten, J. F. Helv. Chimica Acta 2002, 85, 288) (2.35 g), N-(3-bromo-propyl)-phthalimide (4.49 g) and potassium carbonate (10.53 g) were mixed in acetonitrile (25 mL) and refluxed for 12 h. The reaction mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was redissolved in dichloromethane and the insoluble residue filtered off. The filtrate was washed with water, dried over magnesium sulfate, and concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (Merck SuperVarioPrep 90 g column, Si60 15-40 μm), eluted with methanol/dichloromethane, 4:96 to give 5-(3-phthalimido-propyloxy)-1,3-bis-(hydroxymethyl)benzene (1.45 g):
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[C:6]=1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32].[H-].[Na+].Cl[C:36]1[N:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][N:37]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:43][O:42][C:39]1[CH:38]=[N:37][C:36]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[C:6]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[N:41][CH:40]=1
Reactant: CCCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCO)c1Oc1ccccc1OC
Reactant: COc1cnc(Cl)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCOc2ncc(OC)cn2)c1Oc1ccccc1OC
Temperature: 75 °C
Yield: 53.7 %

Procedure:
n-Propanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (92 mg) was dissolved in THF (6 ml). Sodium hydride (40 mg) and 2-chloro-5-methoxy-pyrimidine (92 mg) were added and the mixture was heated to 75° C. for 6 h, then poured onto water, acidified with solid citric acid and the precipitate was filtered off. The crude material was purified by crystallization from methanol to give n-propanesulfonic acid [6-[2-(5-methoxy-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (61 mg) as a white powder. LC-MS: tR: 4.10, [M+H]+: 570.22.
Reaction SMILES: NC[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.F[C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][C:15]=1[N+]([O-])=O.[C:24](=O)([O-])[O-].[K+].[K+].ClCCl>CN(C=O)C>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([C:5]2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=[CH:3][CH:4]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-c1ccc(C)cc1
Yield: 94.9 %

Procedure:
A mixture of methyl 4-aminomethylbenzoate (0.50 g) (obtained by acid-catalysed esterification of 4-aminomethylbenzoic acid), 2,5 difluoronitrobenzene (0.40 g) and potassium carbonate (0.35 g) in DMF (5 ml) was heated at 100° for 5 hours. The mixture was cooled, dichloromethane (20 ml) was added and insoluble material was removed by filtration. The solvent was evaporated and the residue recrystallised from methanol/ethyl acetate to give methyl 4-N-(4-fluoro-2-nitrophenyl)aminomethylbenzoate (B) (0.54 g) as orange needles, m.p. 144°-146° C.; NMR (CDCl3): 3.92(s, 3H), 4.61(d, 2H), 6.70(dd, 1H), 7.17(ddd, 1H), 7.62(d, 2H), 7.93(dd, 1H), 8.04(d, 2H), 8.36(br s, 1H); microanalysis found: C, 59.0; H, 4.1; N, 9.0; C15H13FN2O4 requires: C, 59.2; H, 4.3; N, 9.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[I:26]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][I:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCO)ccc1Cl
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCI)ccc1Cl
Yield: 88.4 %

Procedure:
2-Chloro-5-(3-hydroxypropyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (5.9 g, Example 6d), iodine (6.2 g, 24.4 mmol), triphenylphosphine (6.4 g, 24.4 mmol) and imidazole (1.66 g, 24.4 mmol) were stirred in dichloromethane (100 ml) at room temperature for 1 h. The reaction was quenched with sat. aq. Na2S2O3 and the layers were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (Na2SO4), concentrated and purified by column chromatography on silica (eluting with EtOAc:isohexane/1:3) to afford the subtitled compound as a pale yellow solid (6.8 g)
Reaction SMILES: C(N1C2C([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=5)[NH:24][CH:23]=4)[CH2:17][CH2:16]3)=CC=CC=2NC1=O)(C)=C.[C:33]([N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38](CCCl)[C:37]1=[O:48])([CH3:35])=[CH2:34].FC1C=C2C(=CC=1)NC=C2CC1CCNCC1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[C:33]([N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=4)[NH:24][CH:23]=3)[CH2:19][CH2:20]2)[C:37]1=[O:48])([CH3:35])=[CH2:34]
Reactant: C=C(C)n1c(=O)[nH]c2cccc(CCN3CCC(Cc4c[nH]c5ccc(F)cc45)CC3)c21
Reactant: C=C(C)n1c(=O)n(CCCl)c2ccccc21
Agent: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCN2CCC(Cc3c[nH]c4ccc(F)cc34)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 10 h

Procedure:
3-Isopropenyl-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}-2H-benzimidazolin-2-one may be prepared in the following manner: the procedure is as in Example 25, starting with 3-isopropenyl-1-(2-chloroethyl)-2H-benzimidazolin-2-one (2.4 g), 4-[(5-fluoro-3-indolyl)methyl]piperidine (2.3 g) and sodium bicarbonate (0.8 g) in a mixture of dimethylformamide (40 cc) and tetrahydrofuran (20 cc). The mixture is heated to boiling for 10 hours and then cooled to a temperature in the region of 20° C. After purification by flash chromatography on a silica column under a stream of nitrogen and moderate pressure (0.5-1.5 bar) with dichloromethane and ethyl acetate as eluents, 3-isopropenyl-1-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}-2H-benzimidazolin-2-one (3 g), m.p. 132° C., is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].C(N(CC)CC)C.[F:37][C:38]([F:44])([F:43])[S:39](Cl)(=[O:41])=[O:40]>ClCCl>[F:37][C:38]([F:44])([F:43])[S:39]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29])(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Yield: 62.1 %

Procedure:
In a similar manner to Step 1 of Example 299, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (300 mg, 0.765 mmol) was dissolved in dichloromethane (12 mL), and the solution was treated with triethylamine (0.533 mL, 3.83 mmol) and trifluoromethanesulfonyl chloride (0.138 mL, 1.30 mmol) under ice-cooling, followed by purification by flash column chromatography (chloroform/methanol=100/0 to 98/2) to obtain 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (249 mg, yield 62%).