Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-])=O)=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2].[ClH:16].C(O)(C)C>CO.[Pd]>[ClH:16].[ClH:16].[CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[CH:9][CH:10]=2)[CH2:5][NH:4]1)[CH3:2]
Reactant: CCC1Cc2ccc([N+](=O)[O-])cc2C=N1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CCC1Cc2ccc(N)cc2CN1

Procedure:
To a pressure bottle charged with 3-ethyl-7-nitro-3,4-dihydroisoquinoline (3.6 g, 17 mmols) dissolved in methanol (100 ml) and saturated isopropanol-HCl (20 ml) was added 10% Pd-C (250 mg), and the reaction hydrogenated for 1 h. The catalyst was removed by filtration and the solvent evaporated to yield 3-ethyl-1,2,3,4-tetrahydroisoquinolin-7-amine dihydrochloride (4.3 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:23][CH3:24])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[O:5])C.[OH-].[Na+:26].[C:27]([OH:30])(=[O:29])[CH3:28]>O1CCCC1>[CH3:24][O:23][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](/[CH:15]=[CH:16]/[C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1)=[N:10][NH:11]2.[C:27]([O-:30])(=[O:29])[CH3:28].[Na+:26]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1ccc2[nH]nc(/C=C/c3ccncc3)c2c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)[O-]
Product: COc1c(C(=O)O)ccc2[nH]nc(/C=C/c3ccncc3)c12
Temperature: 50 °C

Procedure:
150 mg of 4-methoxy-3-[(E)-2-(pyridin-4-yl)-vinyl]-1H-indazole-5-carboxylic acid ethyl ester was dissolved in a mixed solvent of 3 mL tetrahydrofuran/1 mL methanol, added with 0.5 mL of 5N sodium hydroxide aqueous solution, and heated at 50° C. for 4 hours. The reaction solution was neutralized with acetic acid, and the solvent distilled off under reduced pressure, to give 500 mg of the crudely produced title compound as a mixture with sodium acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11](N)=[CH:10][CH:9]=1.N(OC(C)(C)C)=[O:16].CCCCC>COCCOC.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([OH:16])=[CH:10][CH:9]=1
Reactant: CC(C)(C)ON=O
Reactant: Nc1ccc(-c2ccccc2F)nc1
Solvent: CCCCC
Solvent: COCCOC
Solvent: ClCCl
Product: Oc1ccc(-c2ccccc2F)nc1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
3.3 ml (26.6 mmol) of boron trifluoride diethylether complex were cooled to −15° C. Then 2.5 g (13.3 mmol) of 6-(2-fluoro-phenyl)-pyridin-3-ylamine in 5 ml of DME and, subsequently, 1.9 ml (15.9 mmol) of tert-butyl nitrite were added dropwise. Shortly after, a thick precipitate formed. The mixture was diluted with 8 ml of DME and 8 ml of dichloromethane and stirred in an ice bath for 2 h. After addition of 50 ml of pentane, the precipitate was filtered off, dried, and stirred in 50 ml of acetic anhydride at 100° C. for 1 h. After concentration, a sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried and evaporated. The residue was purified by chromatography (silica gel, n-heptane/ethyl acetate 5:1). The obtained product was stirred with a 15% aqueous potassium hydroxide solution and few methanol in an ice bath and subsequently for 2 h at room temperature. After neutralization with 2 N hydrochloric acid, the mixture was extracted with ethyl acetate, and the combined extracts were dried and evaporated. Yield: 871 mg.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([C:10]1[S:11][CH:12]=[C:13]([C:15]([N:17]2[CH2:22][C:21]3([CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[O:20][CH2:19][CH2:18]2)=[O:16])[N:14]=1)[CH3:9]>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([C:10]1[S:11][CH:12]=[C:13]([C:15]([N:17]2[CH2:22][C:21]3([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[O:20][CH2:19][CH2:18]2)=[O:16])[N:14]=1)[CH3:9]
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trifluoroacetic acid (20 mL) was added to a solution of tert-butyl 4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate [Example 26, step a] (24 g) in dichloromethane (100 mL) and the mixture stirred at ambient temperature for 18 hours. The reaction mixture was diluted with toluene (50 mL) and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL), TFA (50 mL) was added and the mixture was stirred for 4 hours. The mixture was diluted with toluene (50 mL), concentrated in vacuo, the residue triturated with ether and the precipitated solid collected by filtration and dried to afford the subtitled compound as a white solid. Yield 28 g.
Reaction SMILES: [C:1]([N:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:8][C:7](=[O:16])[CH2:6][O:5]1)(=[O:3])[CH3:2].[O:17]1CCC[CH2:18]1.C=O>C(N(CC)CC)C>[C:1]([N:4]1[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:8]([CH2:18][OH:17])[C:7](=[O:16])[CH2:6][O:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1OCC(=O)NC1c1ccccc1
Reactant: C1CCOC1
Agent: C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1OCC(=O)N(CO)C1c1ccccc1
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 1.1 g. (5 mmoles) of 2-acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one in 10 ml. of tetrahydrofurane 1 ml. of triethyl amine and 0.4 ml. of a 37% aqueous formaldehyde solution are added. The mixture is allowed to stand at room temperature overnight and is then evaporated to dryness. The residue is triturated with diethyl ether and the product is isolated by filtration. 1.16 g. (93%) of 2-acetyl-3-phenyl-4-hydroxymethyl-tetrahydro-1,2,4-oxadiazin-5-one are obtained, melting at 123° to 126° C. RfA =0.5.
Reaction SMILES: O.[NH2:2]N.Cl.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[NH:16])[NH2:15])=[CH:10][CH:9]=1)([O-:7])=[O:6].[C:17]([NH:20][CH:21]([CH3:29])[C:22](=O)[C:23](OCC)=[O:24])(=[O:19])[CH3:18]>C(O)C>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:15][C:23](=[O:24])[C:22]([CH:21]([NH:20][C:17](=[O:19])[CH3:18])[CH3:29])=[N:2][N:16]=2)=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: CCOC(=O)C(=O)C(C)NC(C)=O
Reactant: N=C(N)c1ccc([N+](=O)[O-])cc1
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)NC(C)c1nnc(-c2ccc([N+](=O)[O-])cc2)[nH]c1=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
7.30 g (7.09 ml, 145.82 mmol) of hydrazine hydrate are added dropwise to 24.50 g (121.5 mmol) of 4-nitrobenzenecarboximidamide hydrochloride from example 1A are in 250 ml of ethanol. The mixture is stirred for one hour at 20° C. After this time, 34.12 g (182.28 mmol) of ethyl 3-(acetylamino)-2-oxobutanoate from example 4A are added in ethanol, and the reaction mixture is stirred for 4 h at a bath temperature of 70–80° C., subsequently for 12 h at 20° C. The mixture is concentrated and the residue is purified by flash chromatography (eluent: ethyl acetate, subsequently dichloromethane/methanol 30:1).
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C(=O)C(Cl)=C(Cl)[C:15](=[O:16])C=1C#N)#N>CO>[C:1]([O:16][CH3:15])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=CC=Cc1ccccc1
Solvent: CO
Product: COC(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), MeOH (15 mL) is taken in a round bottom flask and catalytic amount of AMBERLYST® 15 (0.1 g) is added to it. The mixture is stirred for 20 hrs at room temperature. After completion of the reaction (observed by TLC and GC analysis), the reaction mixture is filtered and washed with MeOH (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Methyl cinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═CH3) is isolated in 98% yield. 1H-NMR (CDCl3, 300 MHz) δ7.56 (1H, d, J=16.55 Hz), 7.34 (2H, m), 7.21 (3H, m), 6.31 (1H, d, J=16.55 Hz), 3.64 (3H, s); 13C-NMR (CDCl3, 75.4 MHz) δ167.2, 144.7, 134.3, 130.2, 128.8, 128.0, 117.8, 51.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1.CO>ClCCl.[Fe](Cl)(Cl)Cl>[CH3:22][O:21][C:17]1[CH:18]=[CH:19][C:20]2[C:6]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:15]=2[CH:16]=1
Reactant: COc1cccc(-c2ccccc2-c2cccc(OC)c2)c1
Agent: Cl[Fe](Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c3ccc(OC)cc3c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 56.5 h
Yield: 70.5 %

Procedure:
Into a flask, 2 g of 1,2-bis(3-methoxyphenyl)benzene was put, and allowed to dissolve in 100 ml of dichloromethane under nitrogen atmosphere. In the solution, 3.25 g of iron(III) chloride was added, and the solution was stirred at room temperature for 56.5 hours. Methanol was added to terminate the reaction, and then the solution was washed by water. The organic layer was purified by silica gel column chromatography, and then recrystallized in a toluene/heptane mixed solvent, and thus 1.4 g of 2,7-dimethoxytriphenylene was obtained. Obtained 2,7-dimethoxytriphenylene was converted to 2,7-dihydroxytriphenylene by boron tribromide, and allowed to react with trifluoromethanesulfonyl chloride, and converted to 2,7-bis(trifluoromethanesulfonyloxy)triphenylene. The product was allowed react with bis(pinacolate)diboron, and thus 2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)triphenylene was synthesized.
Reaction SMILES: [CH2:1]([C:3]1([C:18]#[N:19])[CH2:7][CH2:6][N:5](C(=O)C2C=CC(F)=CC=2)[C:4]1=[O:17])[CH3:2].C(N)CCCCCCC>C1COCC1>[CH2:1]([C:3]1([C:18]#[N:19])[CH2:7][CH2:6][NH:5][C:4]1=[O:17])[CH3:2]
Reactant: CCC1(C#N)CCN(C(=O)c2ccc(F)cc2)C1=O
Solvent: CCCCCCCCN
Solvent: C1CCOC1
Product: CCC1(C#N)CCNC1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 97.6 %

Procedure:
To a solution of 3-ethyl-1-(4-fluorobenzoyl)-2-oxopyrrolidine-3-carbonitrile (11 g) in THF (80 mL) was added octylamine (8.5 mL). The reaction mixture was stirred at room temperature for 60 hr, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.7 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:32])=[CH:4][C:5]([NH:9][C:10](=[O:31])[CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:24][CH3:25])([CH3:23])[CH3:22])=[CH:17][C:16]=2[C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])[CH2:12][CH3:13])=[C:6]([OH:8])[CH:7]=1.[C:33](Cl)(=[O:35])[CH3:34].C[C:38]([N:40](C)C)=[O:39]>C(#N)C>[Cl:32][C:3]1[C:2]2=[N:1][C:33](=[O:35])[CH2:34][C:38](=[O:39])[N:40]=[C:7]2[C:6]([OH:8])=[C:5]([NH:9][C:10](=[O:31])[CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:24][CH3:25])([CH3:23])[CH3:22])=[CH:17][C:16]=2[C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])[CH2:12][CH3:13])[CH:4]=1
Reactant: CC(=O)Cl
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c(N)cc1O
Reactant: CC(=O)N(C)C
Solvent: CC#N
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c2c(c1O)=NC(=O)CC(=O)N=2

Procedure:
In a mixture of 160 ml of acetonitrile and 20 ml of dimethylacetamide was dispersed 40 g of the 5-amino-4-chloro-2-[2-(2,4-di-t-amylphenoxy)butanoylamino]phenol prepared in (1) above, and 6.6 ml of acetyl chloride was added dropwise thereto while refluxing. After stirring while refluxing for 1 hour, the reaction mixture was cooled. The precipitated crystals were collected by filtration and dried to provide 40.8 g of the desired compound.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>C(#N)C>[C:10]([N:2]1[CH2:3][CH:4]2[CH2:8][C:7](=[O:9])[CH2:6][CH:5]2[CH2:1]1)(=[O:12])[CH3:11]
Reactant: O=C1CC2CNCC2C1
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2CC(=O)CC2C1
Reaction time: 8 h
Yield: 71.8 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (717 mg, 3 mmol) was dissolved in 20 mL of acetonitrile, and acetic anhydride (0.42 mL, 4.5 mmol) and triethylamine (0.98 mL, 9 mmol) were then added to the solution in an ice-water bath. Upon completion of the addition, the reaction mixture was then stirred overnight in an ice-water bath. The solvent was evaporated, and water (50 mL) was then added to the residue. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-acetyl-hexahydro-cyclopenta[c]pyrrol-5-one 5a (0.36 g, yield 72%) as a colorless oil.
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C(OCC)C>O>[C:17]1(=[O:22])[N:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12
Reactant: Nc1n[nH]c2ccccc12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccccc12
Yield: 87 %

Procedure:
To 50 ml of dioxane were added 5.0 g of 3-aminoindazole thus obtained and 6.68 g of phthalic anhydride, and the mixture was stirred for 5 hours at 120° C. After the mixture was condensed under reduced pressure, the condensed residue was added with 30 ml of diethyl ether and stirred under cooling with ice and water for 30 minutes to separate crystals. Then the crystals were obtained by filtration and dried under reduced pressure to give 8.6 g of 3-phthalimidoindazole having the following analytical values in a yield of 87%.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])(Cl)[Cl:3].[CH3:6][C:7]1[CH2:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([Li])CCC.[Cl-].[Li+]>CCCCCC.C(OCC)C.C1COCC1>[CH3:1][Si:2]([Cl:3])([CH3:5])[CH:15]1[C:14]2[C:9](=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:6]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2cccc(-c3ccccc3)c2C1
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)Cl
Reaction time: 3 h

Procedure:
23 g (180 mmol) of dimethyldichlorosilane was dissolved in 200 ml of dry n-hexane (dried over Na-K alloy), to which was added a solution of 2-methyl-7-phenylindenyllithium (i.e., a solution of 7.4 g (36 mmol) of 2-methyl-7-phenylindene in 70 ml of dry diethyl ether to which was dripped down 22.5 ml of a 1.6 M hexane solution of n-butyllithium at -78° C., followed by stirring at room temperature for 3 hours and by addition of 50 ml of THF) under ice cooling. The mixture was stirred as was at room temperature for 3 hours to deposit white salt of lithium chloride. After standing the mixture so that the white salt precipitated, the supernatant was extracted with a syringe and transferred into another flask and low boiling components (solvent and unreacted dimethyidichlorosilane) were distilled off under reduced pressure at 8 mmHg to obtain dimethyl(2-methyl-4-phenylindenyl)silyl chloride.
Reaction SMILES: C[CH2:2][N:3]=C=NCCCN(C)C.[C:12]([CH2:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[S:23]([NH:26][C:27]1[C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:35]2[C:30]([CH:31]3[CH2:41][CH:32]3[CH2:33][O:34]2)=[CH:29][CH:28]=1)(=[O:25])=[O:24])(O)=[O:13].Cl.Cl.[CH2:44]([N:46]1[CH2:50][CH2:49][C@H:48](NC)[CH2:47]1)[CH3:45].C(N(CC)CC)C>C(Cl)Cl>[CH2:44]([N:46]1[CH2:50][CH2:49][C@@H:48]([CH2:2][NH:3][C:12]([CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[S:23]([NH:26][C:27]2[C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:35]3[C:30]([CH:31]4[CH2:41][CH:32]4[CH2:33][O:34]3)=[CH:29][CH:28]=2)(=[O:24])=[O:25])=[O:13])[CH2:47]1)[CH3:45]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CC(=O)O)ccc2c1OCC1CC21
Reactant: CCN1CC[C@H](NC)C1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC[C@@H](CNC(=O)Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 351.4 %

Procedure:
EDAC (0.058 g) was added to a stirred solution of methyl (1aRS,7bSR)-5-(2-carboxymethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 83, 0.109 g) in DCM (3 mL) and the mixture was stirred at room temperature for 10 minutes. A solution of N—((S)-1-ethylpyrrolidin-3-yl)-N-methylamine dihydrochloride (Intermediate 127, 0.102 g) and triethylamine (0.151 g) in DCM (3 mL) was added and the mixture stirred for 17 hours. The mixture was evaporated in vacuo and the residue was dissolved in dioxane (4 mL) and the mixture was heated at 75° C. for 20 hours. After cooling, the mixture was diluted with DCM and water and filtered through a phase separator. The filtrate was evaporated in vacuo and the residue was combined with an identical reaction carried out earlier. The material was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-50% to give methyl (1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidin-3-yl)methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (0.48 g) as a light brown foam.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([C:34]([N:36]2[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]2)=[O:35])[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([C:34]([N:36]5[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]5)=[O:35])[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C(C1CNC1)N1CC[C@H](O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(=O)N4CC[C@H](O)C4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.9 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (75 mg, 0.19 mmol), azetidin-3-yl-((S)-3-hydroxypyrrolidin-1-yl)methanone (65 mg, 0.38 mmol), and 4 Å molecular sieves (250 mg) in 1,2-dichloroethane (2 mL) was stirred at RT for 4 h. Sodium triacetoxyborohydride (81 mg, 0.38 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 60 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The crude residue was loaded on an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH and the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to afford 460 as an off-white solid (32 mg, 30%). LCMS (Method I): RT 2.33 min, [M+H]+ 546. 1H NMR (400 MHz, CDCl3): δ 7.98-7.93 (1 H, m), 7.71-7.70 (1 H, m), 7.22 (2 H, s), 4.49 (2 H, s), 4.31 (4 H, s), 3.83-3.81 (8 H, m), 3.52-3.50 (9 H, m), 3.32-3.30 (2 H, m), 2.04-1.88 (3 H, m), 1.40 (3 H, t, J=7.47 Hz)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:8]([NH2:10])=[S:9])[CH2:3][CH2:2]1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH2:23]=O>CO>[O:1]1[CH2:6][CH2:5][N:4]([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:8]([NH:10][CH2:23][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[S:9])[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: NC(=S)C(c1ccccn1)N1CCOCC1
Reactant: C=O
Solvent: CO
Product: S=C(NCN1CCOCC1)C(c1ccccn1)N1CCOCC1
Reaction time: 17 h

Procedure:
2-Morpholino-2-(2-pyridyl)thioacetamide (1.0 g., 0.0042 mole) is dissolved with heating in 30 ml. of methanol. To the warm solution is added 1.0 g. (0.012 mole) of morpholine and 1.84 g. (0.022 mole) of 37% aqueous formaldehyde solution. The resulting solution is refluxed three hours and then stirred for 17 hours. The solvent is evaporated and the residue is recrystallized from methanol/ether to give 2-morpholino-N-morpholinomethyl-2-(2-pyridyl)thioacetamide, m.p. 144°-147°C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[N:11][CH:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[C:15]2[O:16][CH2:17][CH:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[CH:6]=[CH:7][CH:8]=1.C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[N:11][CH:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1COC(c2c(-c3ccccc3)cnnc2-c2cccc(OC)c2)=N1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Br
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1coc(-c2c(-c3ccccc3)cnnc2-c2cccc(OC)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
To a solution of methyl 2-(3-(3-methoxyphenyl)-5-phenylpyridazin-4-yl)-4,5-dihydrooxazole-4-carboxylate (compound 25) (60 mg, 0.16 mmol) in DCM (3 mL), DBU (76 mg, 0.5 mmol), bromotrichloromethane (83 mg, 0.41 mmol) was added at 0° C., stirred for 3 h and then warmed to rt. Reaction was quenched by addition of sat. sodium bicarbonate solution, extracted with DCM (2×25 mL), washed with brine (1×5 mL) and dried over anhydrous Na2SO4. Evaporation of solvent under reduced pressure gave the crude product that was purified by column chromatography (100-200 mesh silica gel, 35% EtOAc-Hexane) to furnish methyl 2-(3-(3-methoxyphenyl)-5-phenylpyridazin-4-yl)oxazole-4-carboxylate (compound 26) (35 mg, 59%) as an off white solid.
Reaction SMILES: [CH2:1]([C:4]1([O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:24](O)[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:5])[CH:2]=[CH2:3].S(Cl)([Cl:40])(=O)=O.ClCCl>N1C=CC=CC=1>[CH2:1]([C:4]1([O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:24]([Cl:40])[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:5])[CH:2]=[CH2:3]
Reactant: C=CCC1(O)O[C@H](COCc2ccccc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCC1(O)O[C@H](COCc2ccccc2)[C@H](Cl)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 15 h

Procedure:
Allyl-2,3,6-tri-O-benzyl-glucopyranose (as per Example 14) (960 mg) was dissolved in dry pyridine and added 65 μL of sulfuryl chloride at 0° C. dropwise. The reaction mixture was stirred at this temperature for 15 hours. Dichloromethane (150 mL) was added and the resulting solution was washed with sodium bicarbonate (2×150 mL) and water (2×150 mL). Solvent removal left the residue which was purified by chromatography on silica gel using hexane-ethyl acetate (5:1) as eluent to provide compound allyl 4-chloro-4-deoxy-2,3,6-tri-O-benzyl-galactopyranose (550 mg).