Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Br:12]N1C(=O)CCC1=O>O1CCCC1.S(=O)(=O)(O)O>[Br:12][C:8]1[C:9]([NH2:11])=[CH:10][C:5]2[O:4][CH2:3][CH2:2][O:1][C:6]=2[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc2c(c1)OCCO2
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: Nc1cc2c(cc1Br)OCCO2
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A solution of 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (1 g, 6.6 mmol) in tetrahydrofuran (15 ml) was cooled to −78 deg C. then treated with 1 drop of concentrated sulphuric acid followed by N-bromosuccinimide (1.2 g, 6.6 mmol). The mixture was allowed to warm to room temperature over 1 hour then evaporated. The residue was dissolved in ether, washed with water then brine, dried and evaporated to afford an oil (1.4 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[C:7]1([CH:13]=[C:14]2[C:19](=[O:20])[C:18](=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][O:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(Cl)(Cl)Cl>CC(C)=O>[S:3]1[CH2:4][CH2:5][N:6]=[C:2]1[NH:1][C:19]1([OH:20])[C:18](=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][O:16][CH2:15][C:14]1=[CH:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1C(=Cc2ccccc2)COCC1=Cc1ccccc1
Reactant: NC1=NCCS1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: OC1(NC2=NCCS2)C(=Cc2ccccc2)COCC1=Cc1ccccc1
Reaction time: 8 h
Yield: 45.5 %

Procedure:
A solution of 2-amino-2-thiazoline (2.2 g, 22 mmole) in 100 ml of acetone is added to a suspension of tetrahydro-3,5-bis(phenylmethylene)-4H-pyran-4-one (5.0 g, 18 mmole) in 50 ml of acetone and heated at reflux temperature for 5 hours and then kept at room temperature overnight. Chloroform (75 ml) is added to the stirred mixture and, after 10 minutes, the product is collected and washed with acetone to give 3.1 g of crude product. When the filtrate, concentrated and resuspended in acetone, is stirred with additional 2-amino-2-thiazoline (2.2 g) at room temperature overnight, another 2.5 g is isolated for a combined yield of 5.6 g (82%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:15][C:16]1[C:21]([F:22])=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][N:17]=1>O1CCOCC1.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:20]=[C:21]([F:22])[C:16]([F:15])=[N:17][CH:18]=2)=[N:3][CH:4]=1
Reactant: CC1(C)OB(c2cnc(F)c(F)c2)OC1(C)C
Reactant: Clc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1cc(-c2ccc(Cl)cn2)cnc1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To a pressure vessel was added 2-bromo-5-chloropyridine (3.0 g, 16 mmol), cesium carbonate (15 g, 47 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (2.5 g, 3.1 mmol), and 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.5 g, 19 mmol) in 1,4-dioxane (120 mL) and water (22 mL). The mixture was flushed with argon, sealed and stirred at 90° C. for three hours. The mixture was concentrated, diluted with dichloromethane and washed with water. Organic extracts were concentrated and purified by MPLC (eluted with 0-10% methanol in dichloromethane) to yield 5-(5-chloropyridin-2-yl)-2,3-difluoropyridine as a yellow solid (2.4 g, 68%). MS m/z=227.2 [M+1]+. Calc'd for C10H5ClF2N2: 226.6.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:16]([C:17]#[N:18])=[CH:15][NH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:14]2[CH:15]=[C:16]([C:17]#[N:18])[C:12]([NH:11][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)=[N:13]2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(Nc2n[nH]cc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Nc2nn(-c3ccc(Cl)cc3)cc2C#N)cc1

Procedure:
3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile (64 mg, 0.244 mmol), copper(II) acetate (66.5 mg, 0.366 mmol), (4-chlorophenyl)boronic acid (76 mg, 0.488 mmol) and pyridine (0.079 mL, 0.976 mmol) were stirred in DCM (8 mL) at room temperature overnight. 2 N HCl was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue twice by MPLC (5-60% EtOAc-hexanes) gave 1-(4-chlorophenyl)-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile as a white solid. 1-(4-chlorophenyl)-5-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile was also isolated.
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[CH:8]1[CH:12]([O:13][C:14](=[O:27])[CH:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:11]([OH:29])([CH3:28])[CH:10]([N:30]2[CH:35]=[CH:34][C:33]([N:36]=CN(C)C)=[N:32][C:31]2=[O:41])[O:9]1)(C)(C)C.[NH4+].[F-]>CO>[NH2:36][C:33]1[CH:34]=[CH:35][N:30]([CH:10]2[O:9][CH:8]([CH2:7][OH:6])[CH:12]([O:13][C:14](=[O:27])[CH:15]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:11]2([OH:29])[CH3:28])[C:31](=[O:41])[N:32]=1
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(N=CN(C)C)nc2=O)C1(C)O
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(CO)OC(n2ccc(N)nc2=O)C1(C)O

Procedure:
In another method to synthesize the compounds of the invention, shown in FIG. 1b, benzoylcytosine, BSA and SnCl4/acetonitrile are reacted with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (1) to form 4-benzoylamino-1-(3,4-dibenzoyloxy-5-benzoyloxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (2a); reacting (2a) with NH3 in methanol and chromatographically separating the product, 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (3), also known as β-D-2′-C-methyl-cytidine; reacting (3) with Me2NCH(OMe)2 in DMF at room temperature for 1.5 hours to form N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine (4); reacting (4) with TBDPSCl and pyridine at room temperature for 6 hours to provide N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (5); reacting (5) with N-Boc-L-valine, DEC and DMAP in THF/DMF at room temperature for 2 days and subjecting the product formed from this reaction to HPLC in order to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylaminomethyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (6); refluxing (6) with NH4F in MeOH for about 3 hours to remove the silyl and amino-protecting groups, and subjecting the product to chromatographic purification to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester (7); and finally reacting (7) with HCl in EtOAc at room temperature to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (8) as a final product.
Reaction SMILES: Cl[C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[SH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]([CH:4]=[O:5])[C:2]=1[S:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CCOC(=O)CCCS
Product: CCOC(=O)CCCSc1c(Cl)cccc1C=O

Procedure:
Ethyl 4-(2-chloro-6-formylphenylthio)butyrate was synthesized from 2,3-dichlorobenzaldehyde and ethyl 4-mercaptobutyrate in the same manner as Example 2. After column chromatography, vacuum concentration yielded ethyl 4-(2-chloro-6-formylpehylthio)butyrate (Yield 70%) as a yellow oily matter.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCOC(C)=O>[Pd].CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=CC(=O)c2cccc(O)c2)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(CCC(=O)c2cccc(O)c2)cc1OC
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A solution of 3,4-Dimethoxy-3'-hydroxy chalcone (4) (10 g, 35.2 mmol) in a 1:1 mixture of EtOAc:Acetone (40 mL) was treated with 10% Pd on Carbon (500 mg) and the mixture hydrogenated at 40-50 psi pressure of H2 for 3 h. The reaction mixture was filtered through a pad of Celite with the aid of acetone and the filtrate concentrated to afford a crude solid. The crude solid was triturated with EtOAc and filtered to afford 7.83 g (78%) of white solids which proved to be of ~90% purity by 1H NMR analysis: 1H NMR (CDCl3, 300 MHz) 7.56 (s, 1H), 7.55, (d, J=2.2 Hz, 1H), 7.53-7.33 (m, 1H), 7.10 (dd, J=7.9, 2.4 Hz, 1H), 6.80-7.79 (m, 3H), 6.61 (s, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 3.28 (t, J=7.9 Hz, 2H), 3.02 (t, J=7.9 Hz, 2H); 13C NMR (CDCl3, 75 MHz) 200.6, 156.9, 149.3, 147.8, 138.6, 134.2, 130.3, 121.1, 120.6, 115.0, 112.4, 111.8, 56.3, 41.2, 30.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: C1CCNC1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)N2CCCC2)cc1Cl

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to pyrrolidine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyrrolidine-1-carbonyl)benzamide. MS (Q1) 441 (M)+.
Reaction SMILES: COCCOC.[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH2:22][CH:23]([CH2:26][CH3:27])[CH:24]=O)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Zn].O>[CH2:26]([CH:23]1[CH:24]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21][CH2:22]1)[CH3:27]
Reactant: CCC(C=O)CSc1ccccc1C(=O)c1ccccc1
Agent: [Zn]
Solvent: COCCOC
Solvent: O
Product: CCC1C=C(c2ccccc2)c2ccccc2SC1
Yield: 77.3 %

Procedure:
To a mixture of 2.61 g (0.04 mole) of zinc dust and 60 mL of DME was added 7.5 g (0.048 mole) of TiCl3. The reaction mixture was held at reflux for 2 h. A solution of 2.98 g (0.01 mole) of 11 was added dropwise in 1 h. The reaction mixture was held at reflux for 18 h, cooled and poured into water. The organic was extracted into ether. The ether layer was washed with brine and filtered through Celite. The filtrate was dried over MgSO4 and concentrated. The residual oil (2.5 g) was purified by HPLC to give 2.06 g (77%) of 12 as an oil in the second fraction.
Reaction SMILES: C(N(CC)CC)C.[CH:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl[C:15]1[CH:20]=[CH:19][N:18]([C@@H:21]2[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:25]([O:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:22]2[O:23][CH3:24])[C:17](=[O:47])[N:16]=1>C1COCC1.[Cu]I>[C:8]([C:15]1[CH:20]=[CH:19][N:18]([C@@H:21]2[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:25]([O:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:22]2[O:23][CH3:24])[C:17](=[O:47])[N:16]=1)#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: C#CCCCC
Reactant: CO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1ccc(Cl)nc1=O
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC#Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC)c(=O)n1
Reaction time: 0.08 h

Procedure:
Bis-triphenylphosphine palladium (II) dichloride (422 mg, 4.3 mmole) and copper (I) iodide (114 mg, 4.3 mmole) were suspended in anhydrous THF (100 ml) and degassed with argon for 10 min. The orange suspension was treated with triethylamine (5 ml) and 1-hexyne (2.96 g, 41 mmole) and stirred for 5 min. A solution of 4-chloro-1-(2-O-methyl-3,5,-di-O-benzoyl-β-D-ribofuranosyl)pyrimidin-2-one (6.74 g, 13.9 mmole) in THF (25 ml) was added all at once. The reaction mixture was stirred for 2 hours at room temperature and evaporated to an oil. The residue was purified by silica gel column chromatography. Elution with chloroform (500 ml) and then chloroform/acetone (98:2, 21), pooling of appropriate fractions and evaporation gave a yield of 3.84 g (52.7%).
Reaction SMILES: COC1N=C(C[S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])C([N+]([O-])=O)=CC=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH3:29]
Reactant: COc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2ccc(C)cc2)n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CS(=O)(=O)c1ccc(C)cc1
Temperature: 50 °C

Procedure:
A mixture of 5.0 g (15.5 mmol) of 6-methoxy-3-nitro-2-(toluene-4-sulfonyl methyl)-pyridine and 1.8 mL (16 mmol) of ethyl bromoacetate is dissolved in 20 mL of DMF. To this solution is added 4.4 g (32 mmol) of K2CO3 and the reaction mixture is heated to 50° C. for 18 hours. The reaction mixture is cooled to room temperature and diluted with 300 mL of water. The mixture is extracted with ethyl acetate. The ethyl acetate extracts are dried (Na2SO4) and evaporated to yield 7.2 grams of 6-methoxy-3-nitro-pyridin-2-yl]-[toluene-4-sulfonyl]-acetic acid ethyl ester. 1H NMR (CDCl3) δ8.30 (d, 1H), 7.60 (d, 2H), 7.30 (d, 2H), 6.80 (d, 1H), 6.30 (m, 1H), 4.0 (q, 2H), 3.80 (s, 3H), 3.60 (m, 1H), 3.10 (m, 1H), 2.40 (s, 3H), 1.10 (t, 3H). Mass spectrum: m/e=409.0 (p+1). TLC (7/3: hexanes/ethyl acetate) Rf=0.5.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(N(CC)CC)C>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([NH:19][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(C2(N)CCCC2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccc(C2(NC(=O)C(C)(C)C)CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (100 ml), 1-(p-methylphenyl)cyclopentylamine (8.8 g) and triethylamine (6.1 g), and trimethylacetyl chloride (6.0 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. After the benzene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 10.8 g of N-[1-(p-methylphenyl)cyclopentyl]trimethylacetamide. M.P., 166°-167° C.
Reaction SMILES: C([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7][Cl:8])(=O)C.Cl.O>O1CCOCC1>[NH2:28][C:22]1[C:18]2[C:19](=[O:21])[CH:20]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH:4][CH2:5][CH2:6][CH2:7][Cl:8])=[C:10]([F:29])[CH:11]=3)[O:16][C:17]=2[C:25]([F:26])=[CH:24][C:23]=1[F:27]
Reactant: CC(=O)N(CCCCl)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCCl)c(F)c3)cc(=O)c12
Reaction time: 3 h
Yield: 48.8 %

Procedure:
508 mg (1.20 mmol) of the resulting 2-[4-[N-acetyl-N-(3-chloropropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 30 ml of dioxane, 30 ml of concentrated hydrochloric acid was added and the mixture was stirred for 3 hours under heating at reflux. The reaction solution was cooled on ice and adjusted to pH 8 by addition of water thereto, and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 224 mg (49%) of 5-amino-2-[4-(3-chloropropylamino)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][N:12]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:27](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:27]([N:7]1[CH2:8][CH2:9][N:1]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:16][CH2:17][N:18]([C:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:19][CH2:20]2)[CH2:2][CH2:3][N:4]([C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:5][CH2:6]1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C1CNCCN(CCN2CCNCCNCC2)CCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCN(CCN3CCN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CCN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CC3)CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
From 1,2-Bis(1,4,7-triazacyclononane)ethane (1.1.28), potassium carbonate and trityl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:29])[CH:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:16][OH:17])=[CH:9][CH:8]=1)=[O:5])[CH3:2].[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:29])[CH:15]([NH:18][S:19]([C:22]2[CH:23]=[CH:24][C:25]([I:28])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH2:16][O:17][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(CO)NS(=O)(=O)c2ccc(I)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(I)cc2)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-hydroxy-2-(4-iodobenzenesulfonylamino)propanamide (2.60 g) was reacted with mesyl chloride to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (2.69 g).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=[C:15]2[C:10]=1[C:11]1[CH2:28][CH2:27][CH2:26][CH2:25][C:12]=1[C:13](=[O:24])[O:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1COCC1>[Si:1]([O:8][C:9]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=[C:15]2[C:10]=1[C@H:11]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:12]1[C:13](=[O:24])[O:14]2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCCCc1cc(O[Si](C)(C)C(C)(C)C)c2c3c(c(=O)oc2c1)CCCC3
Solvent: C1CCOC1
Product: CCCCCc1cc2c(c(O[Si](C)(C)C(C)(C)C)c1)[C@H]1CCCC[C@H]1C(=O)O2
Yield: 81.2 %

Procedure:
30 g (74.9 mmol) of 1-tert-butyldimethylsilyloxy-3-pentyl-7,8,9,10-tetrahydro-benzo[c]-chromen-6-one were hydrogenated to completion on palladium/carbon in THF. The catalyst was filtered off, the solvent was removed in vacuo, and the residue was filtered through silica gel with heptane/ethyl acetate (15:1), giving 24.5 g (81%) of (6aR*,10aS*)-1-tert-butyldimethylsilyloxy-3-pentyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-6-one as a colourless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:12][C:13]3[S:14][C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][C:5]=2[CH:4]=1.CCN(C(C)C)C(C)C.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CC#N>[N:31]1([CH2:2][C:3]2[S:7][C:6]3[CH:8]=[C:9]([O:12][C:13]4[S:14][C:15]5[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=5[N:17]=4)[CH:10]=[CH:11][C:5]=3[CH:4]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: ClCc1cc2ccc(Oc3nc4ccccc4s3)cc2s1
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2sc(Oc3ccc4cc(CN5CCCCC5)sc4c3)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.5 %

Procedure:
To a solution 2-(2-chloromethyl-benzo[b]thiophen-6-yloxy)-benzothiazole (86 mg, 0.26 mmol) in MeCN (3 mL) was added DIEA (0.014 mL, 11 mg, 0.8 mmol) followed by piperidine (0.051 mL, 44 mg, 0.52 mmol) and stirred (rt, 12 h). The reaction mixture was partitioned between DCM (15 mL) and saturated NaHCO3(5 mL). The organic layer was washed with saturated NH4Cl (10 mL), dried, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography to provide the title compound as colorless solid (48 mg, 49%). MS (ESI): mass calcd. for C21H20N2OS2, 380.1; m/z found, 381.1[M+H]+. 1H NMR (400 MHz, CDCl3): 7.79 (d, J=2.3, 1H), 7.75-7.72 (m, 1H), 7.70 (d, J=8.6, 1H), 7.65 (dd, J=8.0, 0.7, 1H), 7.40-7.35 (m, 1H), 7.29 (dd, J=8.6, 2.3, 1H), 7.28-7.21 (m, 1H), 7.13 (5, 1H), 3.75 (5, 2H), 2.55-2.40 (m, 4H), 1.69-1.54 (m, 4H), 1.52-1.32 (m, 2H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[CH:10]=[CH:9][C:8]=1[CH:17]1[CH2:22][CH2:21][CH2:20][C:19](=[N:23]O)[CH2:18]1.O>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[CH:10]=[CH:9][C:8]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([NH2:23])[CH2:18]1
Reactant: COCOc1ccc(C2CCCC(=NO)C2)c(OCOC)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCOc1ccc(C2CCCC(N)C2)c(OCOC)c1
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
Nickel chloride hexahydrate (77 mg) and sodium borohydride (24 mg) were added to a stirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanone oxime (50 mg) in methanol (2 ml). After 0.5 hr, water was added until effervescence ceased, the reaction mixture was filtered, and the residue was washed thoroughly with methanol. The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by flash column chromatography (SiO2, dichloromethane/methanol, 9:1 v/v) to furnish the title compound as a colourless oil (31 mg, 65%) and a mixture of diastereoisomers; m/z (ES+) 295 (M+H)+.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([S:14](=[O:17])(=[O:16])[NH2:15])[S:11][C:10]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([S:14](=[O:16])(=[O:17])[NH2:15])[S:11][C:10]=2[CH:18]=1)[CH:2]=[CH2:3]
Reactant: NS(=O)(=O)c1cc2ccc(O)cc2s1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCOc1ccc2cc(S(N)(=O)=O)sc2c1
Reaction time: 24 h

Procedure:
Allyl bromide (2.07 ml, 24.0 mmol) was added dropwise to a stirred solution of 6-hydroxy-2-sulfamoylbenzo[b]thiophene (5.0 g, 22.0 mmol) in dimethylsulfoxide (15.0 ml). A solution of K2CO3 (3.34 g, 24.0 mmol) in water (7.5 ml) was added dropwise to the reaction solution at 25° C. After 24 hours, the reaction mixture was diluted with water (50 ml). The solid that formed was collected and dried, 3.75 gm (13.9 mmol), m.p. 101°-102° C.