Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH:28]([N:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:47]([F:48])=[CH:46][N:45]=[C:44]([NH:49][CH:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[N:43]=2)=[CH:38][C:37]1=[O:56])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)(C(C)(C)C)(C)C>C1COCC1>[Cl:35][C:31]1[CH:30]=[C:29]([CH:28]([N:36]2[CH:41]=[CH:40][C:39]([C:42]3[C:47]([F:48])=[CH:46][N:45]=[C:44]([NH:49][CH:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)[N:43]=3)=[CH:38][C:37]2=[O:56])[CH2:27][OH:26])[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(c1cccc(Cl)c1)n1ccc(-c2nc(NC3CCOCC3)ncc2F)cc1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1cc(-c2nc(NC3CCOCC3)ncc2F)ccn1C(CO)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
1M Tetrabutylammonium fluoride in THF (0.165 mL, 0.165 mmol) was added to 1-(2-(tert-butyldimethylsilyloxy)-1-(3-chlorophenyl)ethyl)-4-(5-fluoro-2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (0.0307 g, 0.0549 mmol) in THF (3 mL). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated, and the residue was partitioned between water and EtOAc. The EtOAc was washed with brine, dried over MgSO4, filtered, and evaporated to yield a crude product as a film. The crude product was purified by chromatography on a 10 g Biotage SNAP column with EtOAc. Fractions 17-32 contained a glass (16.2 mg). The glass was triturated with water and dried to afford 1-(1-(3-chlorophenyl)-2-hydroxyethyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.0129 g, 0.0290 mmol, 52.8% yield) as a film. 1H NMR (400 MHz, CD3OD) δ 8.33 (d, 1H), 7.84 (d, 1H), 7.43-7.24 (m, 5H), 7.03-6.99 (m, 1H), 6.16-6.12 (m, 1H), 4.32-4.27 (m, 1H), 4.22-4.17 (m, 1H), 4.02-3.94 (m, 3H), 3.57-3.49 (m, 2H), 2.02-1.96 (m, 2H), 1.64-1.54 (m, 2H); m/z (APCI-pos) M+1=445.1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl-].[NH4+]>[Fe].O>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1)OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCC(NC(=O)OCc3ccccc3)CC2)cc1
Temperature: 80 °C
Yield: 91.7 %

Procedure:
[1-(4-Nitro-benzenesulfonyl)-piperidin-4-yl]-carbamic acid benzyl ester (1.3 g, 3.5 mmol) was suspended in a 5:1 mixture of ethanol and water (30 ml). To this solution was added iron powder (0.48 g, 9.1 mmol) followed by saturated ammonium chloride solution (1 ml) and the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (1.25 g, 99% yield) as a brown solid. Tr=1.81 min, m/z (ES+) (M+H)+ 390.
Reaction SMILES: [C:1]([C@H:4]1[C@@H:9]([NH:10]C(OCC2C=CC=CC=2)=O)[CH2:8][CH2:7][C@@H:6]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:5]1)(=[O:3])[CH3:2]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:1]([C@H:4]1[C@@H:9]([NH2:10])[CH2:8][CH2:7][C@@H:6]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Reaction time: 2 h
Yield: 109.2 %

Procedure:
Tert-butyl (1R,3R,4S)-3-acetyl-4-benzyloxycarbonylaminocyclohexylcarbamate (600 mg) in MeOH (5 mL) was charged with 5% Pd/BaSO4 (300 mg). The reaction flask was evacuated and then back-filled with hydrogen; this was repeated three more times. The reaction was stirred under 1 atm of H2 for 2 h and then filtered and concentrated to provide tert-butyl (1R,3R,4S)-3-acetyl-4-aminocyclohexylcarbamate (430 mg). MS (ES+)=279.2 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([C:8]3=[O:15])[CH2:6]1)[CH2:12]2)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([NH:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[OH:15])[CH2:6]1)[CH2:12]2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC12CC3CC(C1)C(O)C(C3)C2
Temperature: 25 °C

Procedure:
A stirred solution of 1-acetamido-4-oxoadamantane (420 mg, 2.0 mmol) in MeOH (20 mL) was cooled in an ice bath and an NaBH4 caplet (1.0 g, 26 mmol) was added. The mixture was stirred over the weekend at rt and evaporated to dryness. The residue was taken up in EtOAc (90 mL), washed with 5% aq HCl (20 mL) and satd aq NaHCO3 (20 mL), and dried over MgSO4. Removal of the solvent left 1-acetamido-4-hydroxyadamantane (170 mg, 40%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:36])[NH:26][C:27]3[C:32]\2=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=O)(C)(C)C.C(OCC)(=O)C.[ClH:43]>>[ClH:43].[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:36])[NH:26][C:27]3[C:32]\2=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 29a from (Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone and ethyl acetate/hydrogen chloride.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[Se:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:18][CH2:17][C:15]1[Se:16][C:12]([C:9]2[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: CC(C)[Si](Oc1ccc(-c2ccc(CO)[se]2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(O)cc2)[se]1
Reaction time: 0.5 h

Procedure:
8.7 g (21.4 mmol) of [5-(4-triisopropylsilanyloxyphenyl)selenophen-2-yl]-methanol are initially introduced in 200 ml of THF, and 50 ml of TBAF (50 mmol, 1 M soln. in THF) are added with ice-cooling. After 30 min at this temperature, the mixture is added to water and extracted with MTBE. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is recrystallised from ethyl acetate. 4-(5-Hydroxymethylselenophen-2-yl)phenol is obtained as a beige solid.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:15])[CH2:13][OH:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:17]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18]1.CCN(C(C)C)C(C)C.CC#N.O>CCCCO>[Br:1][C:2]1[C:3]([N:17]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:15])[CH2:13][OH:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C(CO)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2c(Br)cnc3[nH]cc(NC(=O)CO)c23)C1
Temperature: 135 °C
Yield: 47.6 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxyacetamide (0.200 g, 0.694 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.388 g, 2.08 mmol), and DIEA (0.121 mL, 0.694 mmol, d 0.742) were placed in n-BuOH and heated to 135° C. for 8 hours. The reaction was then cooled to room temperature and concentrated to dryness. The resulting residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-75% CH3CN/water) to give the product (R)-tert-butyl 1-(5-bromo-3-(2-hydroxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.150 g, 48% yield).
Reaction SMILES: [CH2:1]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:9](=O)[CH2:10][CH2:11][C:12]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:30]1([CH2:29][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][CH2:11][C:12]([C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH3:13])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(CCC(=O)N(Cc1ccccc1)Cc1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CCCN(Cc1ccccc1)Cc1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 106.1 %

Procedure:
A solution of the product from Example 7 (1.00 g, 2.15 mmol) in 25 mL of anhydrous tetrahydrofuran (THF) was treated dropwise with lithium aluminum hydride solution (4.3 mL of a 1M solution in THF). The resulting solution was heated at reflux for 18 hours. The reaction was cooled and quenched by the addition of saturated NH4Cl solution and extracted with THF. The combined organic extracts were washed with saturated NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated to give the title compound (1.03 g, 100%) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([S@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>ClCCl.[O-]S([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:16]/[S@@:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccc(Br)cc1
Agent: [Cu+2]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(Br)cc1
Temperature: 37 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a mixture of 4-bromobenzaldehyde, 18-a, (150 g, 0.82 mol) in dichloromethane (1.5 L) were added (R)-2-methylpropane-2-sulfinamide (128 g, 1.06 mol), PPTS (20 g, 0.08 mmol) and anhydrous CuSO4 (394 g, 2.46 mol) and the resulting mixture was stirred at 37° C. overnight. The mixture was then filtrated and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to provide the product, 18-b, (200 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:16]1[CH:17]=[CH:18][C:19]([O:29][C:30]([F:33])([F:32])[F:31])=[C:20]([CH:22]2[C:26](=[O:27])[CH2:25][CH2:24][C:23]2=[O:28])[CH:21]=1>C1(C)C=CC=CC=1.[O-]S(C(F)(F)F)(=O)=O.[Cu+2].[O-]S(C(F)(F)F)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:17]=[CH:18][C:19]([O:29][C:30]([F:31])([F:32])[F:33])=[C:20]([CH:22]3[C:26](=[O:27])[CH2:25][CH2:24][C:23]3=[O:28])[CH:21]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)C1c1cc(Br)ccc1OC(F)(F)F
Reactant: Oc1ccc(Cl)cc1
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C1CCC(=O)C1c1cc(Oc2ccc(Cl)cc2)ccc1OC(F)(F)F
Temperature: 160 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-chlorophenol (0.473 g, 3.69 mmol), cesium carbonate (0.521 g, 1.48 mmol), copper triflate (0.013 g, 0.04 mmol) and powdered 5 Å molecular sieves (0.400 g) is added a solution of 2-(5-bromo-2-trifluoromethoxyphenyl)cyclopentane-1,3-dione (0.249 g, 0.74 mmol) in anhydrous toluene (3.5 ml). The mixture is flushed with nitrogen and heated at 160° C. for 1 hour under microwave radiation, then for a further 1 h at 170° C. After cooling to room temperature the crude product is partitioned between dichloromethane (5 ml) and 2M hydrochloric acid (5 ml), and the organic phase is separated then concentrated in vacuo. The residue is then purified by flash column chromatography on silica gel (ethyl acetate/iso-hexane eluant) to afford 2-[5-(4-chlorophenoxy)-2-trifluoromethoxyphenyl]cyclopentane-1,3-dione as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[CH:13]=[CH:12][C:11](=[O:14])[N:10]1[CH2:15][CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19].[C:22]([C:25]1[CH:80]=[CH:79][C:28]([O:29][CH2:30][CH2:31][O:32][C:33]2[CH:34]=[C:35]([CH2:59][O:60][C:61]3[C:62]([O:77][CH3:78])=[CH:63][C:64]4[C:70](=[O:71])[N:69]5[CH2:72][CH2:73][CH2:74][CH2:75][C@@H:68]5[CH:67]=[N:66][C:65]=4[CH:76]=3)[CH:36]=[C:37]([CH2:39][O:40][C:41]3[C:42]([O:57][CH3:58])=[CH:43][C:44]4[C:50](=[O:51])[N:49]5[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:48]5[CH:47]=[N:46][C:45]=4[CH:56]=3)[CH:38]=2)=[CH:27][CH:26]=1)(=O)[CH3:23]>C(Cl)Cl>[CH3:78][O:77][C:62]1[C:61]([O:60][CH2:59][C:35]2[CH:34]=[C:33]([CH:38]=[C:37]([CH2:39][O:40][C:41]3[C:42]([O:57][CH3:58])=[CH:43][C:44]4[C:50](=[O:51])[N:49]5[CH2:52][CH2:53][CH2:54][CH2:55][C@H:48]5[CH:47]=[N:46][C:45]=4[CH:56]=3)[CH:36]=2)[O:32][CH2:31][CH2:30][O:29][C:28]2[CH:79]=[CH:80][C:25](/[C:22](=[N:21]/[NH:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:10]3[C:9](=[O:8])[CH:13]=[CH:12][C:11]3=[O:14])/[CH3:23])=[CH:26][CH:27]=2)=[CH:76][C:65]2[N:66]=[CH:67][C@@H:68]3[CH2:75][CH2:74][CH2:73][CH2:72][N:69]3[C:70](=[O:71])[C:64]=2[CH:63]=1
Reactant: NNC(=O)CCCN1C(=O)C=CC1=O
Reactant: COc1cc2c(cc1OCc1cc(COc3cc4c(cc3OC)C(=O)N3CCCC[C@@H]3C=N4)cc(OCCOc3ccc(C(C)=O)cc3)c1)N=C[C@H]1CCCCN1C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1OCc1cc(COc3cc4c(cc3OC)C(=O)N3CCCC[C@H]3C=N4)cc(OCCOc3ccc(/C(C)=N/NC(=O)CCCN4C(=O)C=CC4=O)cc3)c1)N=C[C@@H]1CCCCN1C2=O
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanehydrazide trifluoroacetic acid salt (246) (3 mg, 0.0096 mmol), (5Z,5′Z,6aR,6a′R)-3,3′-(5-(2-(4-Acetylphenoxy)ethoxy)-1,3-phenylene)bis(methylene)bis(oxy)bis(2-methoxy-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-12(6aH)-one) (243) (7.5 mg, 0.0093 mmol) and 50 mg 4 Å molecular sieves was stirred in 2 ml of dry 5% HAc in DCM (one day earlier dried by 4 Å molecular sieves) for 2 h, neutralized with 0.5 ml of DIPEA, evaporated and purified on HPLC preparative C-18 column (Φ10 mm×200 mm column, flow rate 9 mL/min and a gradient solvent system going from 80:20 solvent A:B at time 0-5 min to 50:50 A:B at 15 min then to 30:70 A:B at 25 min until to 10:90 A:B at 30 min. Solvent A—water, solvent B—methanol/dioxane (2:1)) and lyophilized to afford a white solid 5.6 mg (61%) of the title compound. MS m/z+ 1066.3 (M+2CH3OH+Na).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[C:26]=1[OH:32])=[O:24]>>[C:23]([C:25]1[C:26]([OH:32])=[C:27]([NH:31][C:19]([C:16]2[CH:17]=[CH:18][C:12]3[O:11][C:10]([CH2:9][O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:14][C:13]=3[CH:15]=2)=[O:21])[CH:28]=[CH:29][CH:30]=1)(=[O:24])[CH3:22]
Reactant: CC(=O)c1cccc(N)c1O
Reactant: O=C(O)c1ccc2oc(COCc3ccccc3)cc2c1
Product: CC(=O)c1cccc(NC(=O)c2ccc3oc(COCc4ccccc4)cc3c2)c1O
Yield: 98 %

Procedure:
Following the process described in example 1 (point K), starting from 2-(benzyloxymethyl)benzofuran-5-carboxylic acid and 3-amino-2-hydroxyacetophenone, the title compound was prepared as a yellowish solid with melting point 92-94° C., which was purified by chromatography through a silica gel column (98% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH2:10][C:11]#[N:12])[N:3]=1.[CH2:13]([NH2:23])[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:19]1[C:20]2[CH:21]=[CH:22][C:14]([CH2:13][NH:23][C:2]3[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH2:10][C:11]#[N:12])[N:3]=3)=[CH:15][C:16]=2[O:17][CH2:18]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: Cc1cc(Cl)nc(SCC#N)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(NCc2ccc3c(c2)OCO3)nc(SCC#N)n1

Procedure:
A stirred mixture of 13.93 g. (0.07 mole) of (4-chloro-6-methyl-2-pyrimidinylthio)acetonitrile, 10.5 g. (0.07 mole) of piperonylamine and 7.42 g. (0.07 mole) of sodium carbonate in 100 ml of ethanol was heated under reflux for five hours. The mixture was filtered and the filtrate was cooled in ice. The precipitate thus formed was collected and recrystallized from absolute ethanol to give 15.7 g. of product, m.p. 115°-118°.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=2[N+:12]([O-])=O)[CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1NC1CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)cc1NC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the title compound from Step D (1.23 g, 6.27 mmol) were added 10% palladium on carbon (0.123 g, 1.16 mmol) and methanol (31.3 mL). The resulting mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The reaction mixture was then filtered through CELITE° using dichloromethane and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0 to 30% ethyl acetate in hexanes) provided the title compound: 1H NMR (500 MHz, CDCl3) δ 6.76 (dd, J=10.9, 2.8 Hz, 1 H), 6.60 (dd, J=8.4, 5.6 Hz, 1 H), 6.34 (ddd, J=11.2, 8.4, 2.8 Hz, 1 H), 4.17 (br s, 1 H), 3.01 (br s, 2 H), 2.42-2.38 (m, 1 H), 0.77-0.72 (m, 2 H), 0.54-0.51 (m, 2 H).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:12])([O-:11])[O-:10])=[C:5]([CH2:13]CBr)[C:4]=1CC)C.Cl[C:19]1C=CC=C[C:20]=1Cl>>[CH2:19]([O:10][P:9]1(=[O:12])[C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=2[CH2:13][O:11]1)[CH3:20]
Reactant: CCc1ccc(P(=O)([O-])[O-])c(CCBr)c1CC
Reactant: Clc1ccccc1Cl
Product: CCOP1(=O)OCc2ccccc21
Yield: 75 %

Procedure:
A mixture of diethyl-2-bromoethylphenylphosphonate (2.2 g, 0.00717 mol) in 25 ml. of 1,2-dichlorobenzene was refluxed for 10 hours. The resulting mixture was vacuum distilled. Fractions containing the benzoxaphosphole were collected and then taken up in a hot mixture of benzene-petroleum ether. The mixture was cooled while adding sufficient benzene to prevent oiling out. The cooled mixture yielded 1-ethoxy-1,3-dihydro-2,1-benzoxaphosphole-1-oxide (1.06 g, 75% yield) as colorless crystals having a melting point of 60° C. and the following analysis:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(N(CC)CC)C.[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([CH:26]=[CH:27]CCl)=[CH:24][CH:23]=1.FC(F)(F)C(O)=O>CS(C)=O.ClCCl.O>[Cl:21][C:22]1[CH:31]=[CH:30][C:25](/[CH:26]=[CH:27]/[CH2:1][N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:24][CH:23]=1
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(/C=C/CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.1 %

Procedure:
A solution of N—BOC-piperazine (4.3 g) and triethylamine (9 ml) in dimethylsulfoxide (40 ml) at 0° C. under nitrogen was treated with 4-chlorocinnamyl chloride (5 g) and the resulting solution was stirred at room temperature for 18 hours, poured into water, extracted with ethyl acetate (three times), dried over sodium sulfate and concentrated in vacuo. The residue was filtered over silica gel to afford crude 4-[(E)-3-(4-Chloro-phenyl)-allyl]-piperazine-1-carboxylic acid tert-butyl ester. This compound was dissolved in dichloromethane (30 ml) and treated with trifluoroacetic acid (10 ml) at room temperature for 18 hours. Concentration afforded 1-[(E)-3-(4-Chloro-phenyl)-allyl]-piperazine (5.8 g), which was characterised by its mass and NMR spectra. MS (ES+) 151/153 (M-piperazine), 237/239 (M+H+).
Reaction SMILES: [Cl-:1].[Cr+3:2].N1C2C=CC=CC=2N=C1CNCC1NC2C=CC=CC=2N=1.[Cl-].[Cl-].[NH:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[CH2:35][N:36]([CH2:43][C:44]1[NH:48][C:47]2[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=2[N:45]=1)[CH2:37]CCCCC.[K+].[Br-]>>[Cl-:1].[Cr+3:2].[NH:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[CH2:35][N:36]([CH2:43][C:44]1[NH:45][C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=1)[CH3:37].[Cl-:1].[Cl-:1]
Reactant: CCCCCCN(Cc1nc2ccccc2[nH]1)Cc1nc2ccccc2[nH]1
Agent: [Cr+3]
Agent: [Br-]
Agent: [Cl-]
Product: CN(Cc1nc2ccccc2[nH]1)Cc1nc2ccccc2[nH]1

Procedure:
3b was synthesised by an analogous procedure to that described for 3a using 2e (1 g, 2.8 mmol) and CrCl3(THF)3 (1.05 g, 2.8 mmol). Yield 1.35 g, 93%. Anal. Calc. for C22H27Cl3CrN5 (in %): C, 50.83; H, 5.24; N, 13.47. Found C, 51.05; H, 5.30; N, 13.38. IR (KBr, cm−1), υ 3502 (NH, m), υ 1621-1527 (ArC═C, C═N, m), δ 1498, 1477, 1431 (N—H, s), υ 1273 (CN, m), δ 751 (CH, s). +FAB-MS: (m/z): 483 ([M-Cl]+), 448 ([M-2Cl]).
Reaction SMILES: [Na].[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][NH2:7])[CH3:3].Cl.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[CH:17][N:18]=[N:19]2)=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([S:29]([NH:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:2][CH3:3])(=[O:30])=[O:31])=[CH:27][CH:28]=3)=[CH:17][N:18]=[N:19]2)=[CH:14][CH:13]=1
Reactant: CCN(CC)CCN
Reactant: O=S(=O)(Cl)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: [Na]
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNS(=O)(=O)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Temperature: 5 °C

Procedure:
A mixture of anhydrous sodium carbonte (3.08 g) and N,N-diethylethylenediamine (0.43 ml) in chloroform (30 ml) was vigorously stirred at 5° C. and treated with 4-(7-Chloro-4-cinnolinylamino)benzenesulphonyl chloride hydrochloride (1.0 g). The mixture was stirred at room temperature for 11/2 hours and then filtered. The filtrate was evaporated to give a residue that crystallised from ethanol to give the title compound (0.456 g), m.p. 175°-76° C.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[C@H:41]1[O:58][CH2:57][C@H:52]([O:53][C:54](=[O:56])[CH3:55])[C@@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@@H:42]1[O:43][C:44](=[O:46])[CH3:45])(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[Br:1][C:2]1[N:3]([C@H:57]2[O:58][CH2:41][C@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@@H:52]2[O:53][C:54](=[O:56])[CH3:55])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1cc2nc(Br)[nH]c2cc1Cl
Reactant: CC(=O)O[C@H]1OC[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)OC[C@@H]1OC(C)=O
Temperature: 50 °C
Yield: 56 %

Procedure:
As described in General Procedure III, 2-bromo-5,6-dichlorobenzimidazole (1.0 g, 3.8 mmol), N,O-bis(trimethylsilyl) acetamide (Aldrich, 1.0 ml, 4.1 mmol), and 1,2-dichloroethane (Aldrich Sure Seal, 25 ml) were combined and refluxed under nitrogen for 0.5 h. The solution was cooled to 50° C. and trimethylsilyl trifluoromethanesulfonate (Aldrich, 0.8 ml, 4.1 mmol) was added. Immediately, 1.4 g (4.4 mmol) solid 1,2,3,4-tetra-O-acetyl-beta-L-xylopyranose was added. The solution was stirred under nitrogen at reflux for 0.25 h, then poured into 7% aqueous sodium bicarbonate and extracted with dichloromethane. The organic layers were dried with magnesium sulfate (anhyd), filtered, and evaporated. The crude residue was crystallized from chloroform and hexane to give 1.11 g (56% yield) of 2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-L-xylopyranosyl)-1H-benzimidazole. 1H NMR (CDCl3) δ7.80 (s,1H), 7.76 (s, 1H), 5.68-5.64 (m, 1H), 5.55-5.51 (m, 1H), 5.32-5.25 (m, 1H), 4.48-4.43 (dd, 1H), 3.69-3.61 (t, 1H), 2.15 (s, 3H), 2.10 (s, 3H), 1.90 (s, 3H).