Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13](Cl)[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[CH:10]=[N:9][C:8]=2[CH:19]=1.[CH3:20]I.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.Cl>C1(C)C=CC=CC=1.CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:20])[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:9][C:8]=2[CH:19]=1
Reactant: C1CNCCN1
Reactant: CI
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1N2Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1c2ccc(Cl)cc2N=C(N2CCNCC2)c2ccccc21
Reaction time: 1 h
Yield: 54.8 %

Procedure:
NaH (12 mg, 0.29 mmol, 60% in mineral oil) was added to a mixture of 8,5-dichloro-5H-dibenzo[b,e][1,4]diazepine (160FE64) (50 mg, 0.19 mmol) in toluene (1.5 mL) and DMF (0.5 mL). MeI (24 μL, 0.38 mmol) was then added. The resulting mixture was stirred for 1 h then quenched by addition of saturated aqueous NaHCO3-solution (2 mL). The mixture was extracted with diethyl ether, and the combined organic phases were dried (Na2SO4) and concentrated. The residue was taken up in toluene (2.0 mL), piperazine (98 mg, 1.1 mmol) was added, and the resulting mixture was stirred at 100° C. for 1 h. Aqueous HCl (1 mL, 2M) and EtOAc (2 mL) was then added to the mixture. The phases were separated and the aqueous phase was extracted with EtOAc (2 mL) and then aqueous NaOH (2 mL, 2 M) was added. The basic aqueous phase was extracted with EtOAc (3×2 mL) and the combined organic phases were dried (Na2SO4) and concentrated. The residue was dissolved in DMF and purified on HPLC to give 34 mg of the title compound (189JO25A). MS (ESI) 327 (MH+). Purity for MH+ (UV/MS) 100/100.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:27][O:28][CH2:29][CH2:30][OH:31]>C(Cl)Cl.C(O)(=O)C>[OH:31][CH2:30][CH2:29][O:28]/[N:27]=[C:23](/[C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C:11]3([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH2:13][CH2:12]3)=[N:15][N:16]=2)[N:19]=1)\[CH3:24]
Reactant: CC(=O)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Reactant: NOCCO
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: C/C(=N\OCCO)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1

Procedure:
A solution of 1-(3-(1-(quinolin-6-yl)cyclopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (30 mg, 0.09 mmol) (59.4) and 2-aminooxy-ethanol hydrochloride (intermediate S) (14 mg, 0.18 mmol) in 4 mL of DCM and 0.5 mL of acetic acid was stirred at 40° C. overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with a EtOAc/methanol gradient to afford the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.84 (t, 1H), 8.30 (d, 1H), 8.25 (d, 1H), 7.93-7.91 (m, 2H), 7.71-7.68 (m, 2H), 7.51 (dd, 1H), 4.73 (t, 1H), 4.23 (t, 2H), 3.65 (q, 2H), 2.02 (s, 3H), 1.78-1.75 (m, 2H), 1.68-1.64 (m, 2H). LCMS (method A): [MH]+=389, tR=4.55 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Fc1ccc(-c2noc(-c3cccc(Br)c3)n2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: Fc1ccc(-c2noc(-c3cccc(-c4cccnc4)c3)n2)nc1
Yield: 50.2 %

Procedure:
A mixture of 3-(5-fluoro-pyrid-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole (100 mg, 0.313 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (102 mg, 0.624 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 50.8 mg, 0.044 mmol), in a solution of ethylene glycol dimethyl ether (2 mL) and 2M sodium carbonate (2 mL) was heated in a sealed vial at 110° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate afforded 50 mg (50.2%) 3-(5-fluoro-pyrid-2-yl)-5-[3-(3-pyridyl)phenyl]-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 8.91 (d, 1H), 8.69 (d, 1H), 8.64 (d, 1H), 8.49 (s, 1H), 8.28 (m, 2H), 8.00 (m, 1H), 7.84 (dd, 1H), 7.69 (t, 1H), 7.60 (td, 1H), 7.44(dd, 1H).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[NH2:17][C:18]1[C:19]([Cl:33])=[C:20]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([F:26])[CH3:25]>O.O1CCOCC1>[Cl:33][C:19]1[C:18]([N:17]=[C:1]=[S:2])=[C:31]([Cl:32])[CH:30]=[CH:29][C:20]=1[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:25])([F:26])[CH3:27]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(C)(F)C(=O)NCc1ccc(Cl)c(N)c1Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(F)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl

Procedure:
1,1′-Thiocarbonyldi-2-pyridone (1.21 g, 5.2 mmol) is added to a mixture of N-(3-amino-2,4-dichloro-benzyl)-2-methyl-2-fluoro-propionamide (1.32 g, 4.7 mmol) and dioxane (25 mL) and it is stirred at reflux for 2 d. The mixture is diluted with water, most of the dioxane is removed under reduced pressure and the resulting precipitate is collected by filtration, washed with water and dried.
Reaction SMILES: [CH:1]1[C:15](=[O:16])[N:14]=[C:13]2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3[O:12]2)[CH:2]=1.C1C=CN=CC=1.[FH:23]>O1CCOCC1>[F:23][C@@H:5]1[C@H:6]([OH:11])[C@@H:7]([CH2:9][OH:10])[O:8][C@H:4]1[N:3]1[CH:2]=[CH:1][C:15](=[O:16])[NH:14][C:13]1=[O:12]
Reactant: F
Reactant: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Yield: 75 %

Procedure:
2,2'-Cyclouridine is treated with a solution of 70% hydrogen fluoride/pyridine in dioxane at 120° C. for ten hours to provide after solvent removal a 75% yield of 2'-deoxy-2'-fluorouridine. The 5'-DMT and 3'-cyanoethoxydiisopropyl-phosphoramidite derivitized nucleoside is obtained by standard literature procedures (Gait, Ed., Oligonucleotide Synthesis. A Practical Approach, IRL Press, Washington, DC (1984)], or according to the procedure of Example 4-a.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:34])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH2:30][NH:29][CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17].N12CCCN=C1CCCCC2.[C:46]([O:50][CH2:51][CH3:52])(=[O:49])[CH:47]=[CH2:48]>C(#N)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:34])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH2:30][N:29]([CH2:48][CH2:47][C:46]([O:50][CH2:51][CH3:52])=[O:49])[CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCNC2
Reactant: C=CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)CCN1CCc2c(ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2C)C1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
To a suspension of 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-1,2,3,4-tetrahydroisoquinoline trifluoroacetate (Example 10; 90 mg; 0.18 mmol) in acetonitrile (3 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 0.16 ml; 1.09 mmol). Ethyl acrylate (0.03 ml; 0.27 mmol) was added to the solution and the resulting mixture stirred at 70° C. for 0.5 h. The mixture was cooled to room temperature and the solvent removed. The residue was partitioned between ethyl acetate and brine, and the aqueous layer further extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (90 mg).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]([O:39][C@H:40]1[C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[CH:43](OC(=O)C)[O:42][C@@H:41]1[C:53]1[N:54]=[N:55][N:56]([CH2:58][CH3:59])[N:57]=1)(=[O:38])[CH3:37].C[Si](OS(C(F)(F)F)(=O)=O)(C)C>ClC(Cl)(Cl)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:46]([O:45][C@@H:44]1[C@H:40]([O:39][C:36](=[O:38])[CH3:37])[C@@H:41]([C:53]2[N:54]=[N:55][N:56]([CH2:58][CH3:59])[N:57]=2)[O:42][C@H:43]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:20])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:48])[CH3:47]
Reactant: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CCn1nnc([C@H]2OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(C(=O)NCCN5CCCCC5)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reaction time: 8 h
Yield: 74.4 %

Procedure:
A suspension of 6-[(2,2-diphenylethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide (Preparation 11) (0.2 g, 0.42 mmol) in 1,1,1-trichloroethane (10 ml) was treated with N,O-bis(trimethylsilylacetamide) (0.65 ml, 2.65 mmol) and the mixture was heated under reflux for 2 hours. The solvent was removed under reduced pressure and the residue was twice azeotroped with toluene. The residue was dissolved in toluene (5 ml) and treated sequentially with a solution of (2R,3R,4R)-4,5-bis(acetyloxy)-2-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3-furanyl acetate (WO-A-9967265) (0.175 g, 0.51 mmol) in toluene (5 ml) and then trimethylsilyltriflate (0.1 ml, 0.55 mmol). The mixture was heated under reflux for 3 hours and then allowed to stand at room temperature overnight. The solution was diluted with ethyl acetate (40 ml), washed sequentially with saturated aqueous sodium hydrogen carbonate solution (20 ml) and brine (20 ml) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (93:7 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to afford the title compound (0.235 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:15](=[S:22])[N:16]([CH3:21])[CH2:17][C:18]([OH:20])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[OH:55][CH:56]1[O:64][C@H:63]([CH2:65][OH:66])[C@@H:61]([OH:62])[C@H:59]([OH:60])[C@H:57]1[NH2:58]>CN(C)C=O>[CH3:14][O:13][C:12]1[C:3]([C:2]([F:1])([F:23])[F:24])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:15]([N:16]([CH2:17][C:18]([NH:58][C@H:57]([C@H:59]([C@@H:61]([C@@H:63]([CH2:65][OH:66])[OH:64])[OH:62])[OH:60])[CH:56]=[O:55])=[O:20])[CH3:21])=[S:22])=[CH:7][CH:6]=[CH:5]2
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: COc1ccc2c(C(=S)N(C)CC(=O)O)cccc2c1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=S)N(C)CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO)cccc2c1C(F)(F)F
Reaction time: 1 h

Procedure:
N-[[5-(Trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methylglycine (3.57 g, 0.010 mol), 1-hydroxybenzotriazole (2 g, 0.015 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.3 g, 0.012 mol) and triethylamine (3.5 mol, 0.025 mol) were dissolved in dimethylformamide (25 ml). The mixture was cooled in ice and stirred for 1 hour. D-Glucosamine hydrochloride (2.38 g, 0.011 mol), and additional triethylamine (2.0 mol) were added to the cold reaction mixture. The reaction mixture was stirred at 0° C. for 1 hour, and at room temperature over night and evaporated. The residue was triturated with water and filtered. The solids were washed with H2O, 1NHCl, 5% NaHCO3, H2O and crystallized from 8/5 H2O/MeOH to yield 3.63 g, 67.7%. The product was further purified by recrystallization from boiling methanol (3.1 g), m.p. 166°-169° C. (dec.) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([C:15](OCC)=[O:16])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C[AlH]CC(C)C)C.[NH4+].[Cl-].O>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([CH2:15][OH:16])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxylate (Intermediate 10) (0.33 g, 1.09 mmol) in THF was added a 1M solution of DIBAL-H in toluene (2.3 mL, 2.1 eq) and the reaction was stirred at room temperature for 2 hours. The reaction was not completed. Two more equivalents of a 1M solution of DIBAL-H in toluene were added and the reaction was stirred for a further 18 hours. Solid NH4Cl was added followed by water and the aqueous phase was extracted with ether, ethyl acetate, dried over sodium sulphate and evaporated. The title compound was obtained as a white powder after recrystallisation from isopropyl ether (170 mg, 60%). LC/MS: m/z 258 (M+H)+ Rt: 2.45 min.
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[S:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][I:16]>CO>[CH:1](=[N:8][N:9]1[CH2:13][CH2:12][N:11]=[C:10]1[S:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[IH:16]
Reactant: CI
Reactant: S=C1NCCN1N=Cc1ccccc1
Solvent: CO
Product: CSC1=NCCN1N=Cc1ccccc1
Product: I

Procedure:
5 g of 1-benzylideneamino-imidazolidine-2-thion are suspended in 40 ml of methanol and treated with 1.7 ml of methyliodide. The mixture obtained is refluxed for ca. one hour and the solvent is evaporated off. 1-Benzylideneamino-2-methylthio-4,5-dihydro-1H-imidazole in the form of a hydroiodide is obtained in solid form, to which 120 ml of water and 70 ml of an anion exchange resin in chloride form (Amberlite IRA-400 (Cl)R) are added. The mixture is stirred for ca. 2 hours at room temperature, filtrated and lyophilized. 1-Benzylideneamino-2-methylthio-4,5-dihydro-1H-imidazole in the form of a hydrochloride is obtained in the form of a lyophilisate.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[CH2:24]([OH:28])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([O:28][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CCCCO
Product: CCCCOc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylthio-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with n-butanol according to the procedure described in Example 59 to afford 2-(n-butyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=407 (M++1); Rt=4.80 min; 1H-NMR 400 MHz (CDCl3): δ 1.00 (t, 3H), 1.50-1.6 (m,2H), 1.80-1.85 (m, 2H), 4.41-4.44 (t, 2H), 7.01 (d, J=9 Hz, 2H), 7.21-7.25 (m, 5H), 8.58 (s, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1.[H][H].Cl.Br[CH:18]([CH3:22])[C:19]([OH:21])=[O:20]>CN(C)C=O.O>[F:3][C:4]([F:12])([F:13])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(Br)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(C(F)(F)F)cc1)C(=O)O
Yield: 75.8 %

Procedure:
To a slurry of 12 g of sodium hydride-oil dispersion (57%) in 100 ml of N,N-dimethylformamide is added 21 g of α,α,α-trifluoro-p-cresol in 10 ml of dimethylformamide and 24 g of 2-bromopropionic acid. After hydrogen evolution, the mixture is heated at 90° C. for 14 hrs. The mixture is cooled, diluted with 100 ml of water, acidified with hydrochloric acid and extracted with ether. The ether extracts are dried (MgSO4) and concentrated to give 23 g of product. A 3.5 g sample is chromatographed over silica gel with solvent hexane-ether-acetic acid (80:20:1) to give 2.3 g of white crystals. Recrystallization from hexane gives crystals, mp 81°-82° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:13](=[C:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)C(=O)C(=Cc1ccccc1)C2
Temperature: 25 °C
Yield: 15 %

Procedure:
6-Methoxy-1-indanone (10 g, 61.2 mmol), benzaldehyde (7.85 g, 74.0 mmol), piperidine (1.05 g, 12.3 mmol), and acetic acid (4.4 g, 74.0 mmol) were refluxed in toluene (150 ml) for 3 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was washed serially with saturated saline and water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting crystals were washed with diethyl ether to provide the title compound (yield 2.3 g, 80%).
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:1][C:2]1[C:10]([O:11][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([C:12]([O:14][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(C(=O)O)c(O)c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1OCc1ccccc1
Temperature: 67 °C
Yield: 48 %

Procedure:
1 (101.798 g, 0.514 mol), benzyl chloride (258 mL, 2.242 mol), KI (25.304 g, 0.140 mol), K2CO3 (664.270 g, 4.806 mol), and 1.3 L DMF were combined in a 5-L 3-neck round-bottom flask, yielding a mixture of dark brown solution and undissolved solid. The flask was fitted with a reflux condenser and mechanical stirrer, and placed in a heating mantle. The reaction mixture was heated at 67° C. for 3 d and filtered. The dark brown, clear filtrate was rotovapped to ˜400 mL of opaque, brown, viscous oil, which was dissolved in ˜600 mL DCM. The opaque, brown solution was filtered and extracted with water (5×500 mL). A small amount of brine was used to break up emulsions. The organic layer was dried with MgSO4 and rotovapped to ˜250 mL of dark brown oil. This oil was purified by silica column chromatography (0-5% MeOH in DCM) to yield a hardened brown oil (48%).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](Cl)=[N:7][N:6]=1>C(O)C>[ClH:4].[Cl:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:2][NH2:3])=[N:7][N:6]=1
Reactant: NN
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: CCO
Solvent: O
Product: Cl
Product: NNc1nnc(Cl)c2ccccc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of hydrazine hydrate (40 ml) in ethanol (120 mL) at 80° C. was added 1,4-dichlorophthalazine (20 g). This reaction, mixture was stirred at 80° C. for 0.5 hours, then left to cool and the product was collected by filtration and dried under vacuum to give 1-chloro-4-hydrazinophthalazine hydrochloride (14.6 g). 1H NMR (250 MHz, DMSO)•4.64 (2H, vbs), 7.2 (1H, vbs), 7.92 (4H, bm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.CC1C=CC(S(O[CH2:38][CH2:39][O:40][CH:41]2[CH2:43][CH2:42]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:38][CH2:39][O:40][CH:41]2[CH2:43][CH2:42]2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CC2)cc1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (30 mg, 0.08 mmol) in anhydrous DMF (1 mL) were added 2-cyclopropoxyethyl 4-methylbenzenesulfonate (intermediate BP) (20 mg, 0.08 mmol) and Cs2CO3 (52 mg, 0.16 mmol). The mixture was stirred at room temperature for 12 h. Then the reaction mixture was poured into water, extracted with EA, washed with brine, dried with anhydrous Na2SO4 and concentrated to an oil. The oil was purified by preparative HPLC to obtain compound BQ (11 mg) as a colorless oil. 1H NMR (CD3OD): δ 7.30 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 4.13 (m, 5H), 3.85 (m, 3H), 3.81 (m, 1H), 3.40 (m, 4H), 3.30 (m, 1H), 0.52 (m, 4H); MS ESI (m/z) 465 (M+H)+, calc. 464.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1C(=O)C2=CC=CC=C2C1=O)=[N+:2]=[N-:3].O.NN>CO>[NH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCCOCCOCCOCCN
Temperature: 25 °C
Yield: 50.5 %

Procedure:
1-Azido-11-phtalimido-3,6,9-trioxaundecane (8, Example 3, 2.0 g, 5.74 mmol), is treated with 1.0 ml 55% hydrazine hydrate in 50 ml abs. methanol and heated to reflux for 2 h. After cooling to room temperature, the mixture is concentrated in vacuo, diluted with 50 ml of water and treated with 5 ml conc. HCl. All precipitate is filtered off, the aqueous filtrate neutralized with NaOH, and the solvent removed in vacuo. The residue is dissolved in dichloromethane, and washed with 3 N NaOH and water. The organic phase is dried over MgSO4 and concentrated in vacuo yielding 0.63 g (2.9 mmol, 51%) of a colourless oil, which is used in the next step without further purification.