Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:35])=[C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=4[CH:34]=3)[CH:14]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:37][OH:38].CCN(CC)CC>C(O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[O:22][C:18]3[CH:17]=[CH:16][C:15]([C:13]4[CH:14]=[C:9]([C:7](=[O:8])[NH:6][C:3]5([C:1](=[NH:2])[NH:37][OH:38])[CH2:4][CH2:5]5)[CH:10]=[CH:11][C:12]=4[CH3:35])=[CH:34][C:19]=3[C:20]=2[C:30]([NH:32][CH3:33])=[O:31])=[CH:28][CH:27]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C#N)CC4)ccc3C)cc12
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=N)NO)CC4)ccc3C)cc12
Temperature: 115 °C

Procedure:
To a mixture of 5-(5-(1-cyanocyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (43.5 mg, 0.093 mmol) in ethanol (1.5 mL) at r.t. under N2 was added hydroxylamine hydrochloride (12.93 mg, 0.186 mmol), followed by Et3N (0.039 mL, 0.279 mmol). The mixture was stirred at reflux (115° C.) for about 4 hours. The mixture was cooled to r.t. and evaporated. The residue was used for the next step without further purification. LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: PHENOMENEX® Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=501.13, HPLC Rt=1.385 min.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:10]2[CH:26]=[CH:27][CH:28]=[CH:29][C:9]=2[N:8]=1)[CH2:2][CH2:3][CH3:4].[F:30][C:31]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>C1(C)C=CC=CC=1.ClC(Cl)C>[CH2:1]([N:5]([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:10]2[CH:26]=[CH:27][CH:28]=[CH:29][C:9]=2[N:8]=1)[C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:39]([F:40])[C:31]=1[F:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1nc2ccccc2n1Cc1ccccc1CN1CCCCC1
Reactant: O=C(Cl)c1cccc(F)c1F
Solvent: CC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCN(Cc1nc2ccccc2n1Cc1ccccc1CN1CCCCC1)C(=O)c1cccc(F)c1F

Procedure:
A solution of 0.9 g (1.7 mmole) of compound D was treated with 10 mL of butyl amine in 50 mL of acetonitrile at room temperature for 2 hr. The resulting solution was concentrated and partitioned between ethyl acetate and 1N NaOH. The organic layer was dried over anhydrous Na2SO4 and concentrated to yield 0.55 g of Butyl-[1-(2-piperidin-1-ylmethyl-benzyl)-1H-benzoimidazol-2-ylmethyl]-amine. 1H NMR (300 MHz, CDCl3) 7.8 (d, 1H), 7.2 (m, 5H), 7.05 (d, 1H), 6.4 (d, 1H), 5.8 (s, 2H), 4.0 (s, 2H), 3.6 (s, 2H), 2.6 (t, 2H), 1.2-1.6 (m, 14H), 0.8 (t, 3H). A quantity of 0.1 mL of a 0.2 M solution of Butyl-[1-(2-piperidin-1-ylmethyl-benzyl)-1H-benzoimidazol-2-ylmethyl]-amine in toluene is treated with 0.15 mL of a 0.2 M solution of 2,3-Difluoro-benzoyl chloride in dichloroethane at room temperature for 1 hr. The resulting mixture was chromatographed on SiO2 with ethyl acetate to yield 9 mg of N-Butyl-2,3-difluoro-N-[1-(2-piperidin-1-ylmethyl-benzyl)-1H-benzoimidazol-2-ylmethyl]-benzamide. LCMS MF=C32H36F2N4O MW=530.6 found 531. B. N-Butyl-2,3-difluoro-N-[1-(4-piperidin-1-yl-but-2-Enyl)-1H-benzoimidazol-2-ylmethyl]-benzamide
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.P([S-])(OCC)(OCC)=[S:12].O>Cl.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([NH2:8])=[S:12])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C#N)cc1
Reactant: CCOP(=S)([S-])OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ccc(C(N)=S)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 67 %

Procedure:
4-Methylthiobenzonitrile (12 g) was dissolved in a solution (130 mL) of 4N hydrogen chloride in ethyl acetate. To this solution was added O,O-diethyl dithiophosphate (15 mL) and the mixture was stirred at room temperature for 22 h. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate. The insoluble material was filtered off and the filtrate was washed with saturated brine, dried and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give the title compound (10 g, yield 67%).
Reaction SMILES: Br[CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[CH:7]([N-:9][CH:10]=[O:11])=[O:8].[Na+]>C(#N)C>[CH:7]([N:9]([CH2:2][C:3](=[O:6])[CH2:4][CH3:5])[CH:10]=[O:11])=[O:8]
Reactant: O=C[N-]C=O
Reactant: CCC(=O)CBr
Agent: [Na+]
Solvent: CC#N
Product: CCC(=O)CN(C=O)C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of bromobutan-2-one (10 g, 66 mmol), and sodium diformylamide (6.8 g, 72 mmol) in acetonitrile (50 mL) was stirred at room temperature for 3 hours, then warmed to 35° C. for 2 hours. The mixture was stirred for a further 48 hours at room temperature, then filtered, washing through with additional acetonitrile (50 mL). The filtrate was evaporated under reduced pressure to afford the title compound as a clear oil, 9.1 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.NO.Cl.CCN=C=NCCCN(C)C.C1C=CC2[N:63]([OH:64])N=NC=2C=1.CCN(CC)CC>CN(C)C=O>[OH:64][NH:63][C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:40])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[CH:32][CH:33]=1)=[O:36]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)NO)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 44.3 %

Procedure:
To a solution of rac 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid prepared in Example 232 (50 mg, 0.09 mmol) in N,N-dimethylformamide (2 mL) was added. NH2OH.HCl (18 mg, 0.26 mmol), EDCI (33 mg, 0.17 mmol), HOBT (21 mg, 0.15 mmol) and NEt3 (0.036 mL, 0.26 mmol). The reaction mixture was heated at 80° C. for 48 h. The mixture was cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by prep-HPLC to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxycarbamoyl-phenyl)-amide as a white solid (24 mg, 47%).
Reaction SMILES: [K:1].[S:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1)([OH:5])(=[O:4])=[O:3].[C:16](O)(=[O:21])[CH2:17][C:18](O)=[O:19].C(OC(=O)C)(=O)C>C(O)(=O)C>[S:2]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16](=[O:21])[CH2:17][C:18](=[O:19])[NH:15][C:13]2=[O:14])=[CH:10][CH:11]=1)([OH:5])(=[O:4])=[O:3].[K:1]
Reactant: NC(=O)Nc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CC(=O)O
Agent: [K]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(=O)N(c2ccc(S(=O)(=O)O)cc2)C(=O)N1
Temperature: 95 °C
Yield: 91.1 %

Procedure:
A mixture of 29.9 g of N-(4-sulfophenyl)urea potassium salt, 15 g of malonic acid and 200 ml of glacial acetic acid was heated to 60° to 70° C with stirring and 300 ml of acetic anhydride was added dropwise to the mixture. After about 50 ml of the acetic anhydride had been added, the mixture dissolved. After all of the acetic anhydride (300 ml) was added, the temperature of the reaction solution increased to 95° C. The reaction solution was stirred for 4 hours and then condensed under reduced pressure so as to precipitate crystals. 700 ml of ethanol was added to the condensed solution and the crystals were completely precipitated. The precipitated crystals were collected by filtration, washed thoroughly with ethanol and dried by heating under reduced pressure to obtain 34.5 g of crystals. The obtained crystals were recrystallized using a 90% methanol aqueous solution and, thereby, 29.3 g of white crystals was obtained. Melting point: above 300° C. Elemental Analysis:
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:24])[CH2:9][CH2:10][C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[C@@H:14]([OH:23])[CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.Cl>N1C=CC=CC=1>[C:25]([O:23][C@@H:14]1[C:15]2[C@:21]([CH3:22])([CH2:20][CH2:19][C:17](=[O:18])[CH:16]=2)[C@@H:11]2[C@H:12]([C@H:7]3[C@:8]([CH3:24])([CH2:9][CH2:10]2)[C@@H:4]([C:2](=[O:3])[CH3:1])[CH2:5][CH2:6]3)[CH2:13]1)(=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3C[C@H](OC(=O)CCC(=O)O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C

Procedure:
Two grams of 6α-hydroxyprogesterone is refluxed for 1 hour in 20 ml. of pyridine with 4 g. of succinic acid anhydride. After cooling, the solution is stirred into ice water and acidified with 1N hydrochloric acid. The smeary precipitation product is separated and dissolved in methylene chloride; the solution is washed with hydrochloric acid and water and evaporated under vacuum. The residue (2.57 g. of foam) is dissolved in methanol, combined with carbon, filtered, and the filtrate concentrated under vacuum. By trituration of the residue with pentane, 2.1 g. of amorphous (3,20-dioxo-4-pregnen-6α-yl) hydrogen succinate is produced. UV: ε238 = 14,100.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]=O)[CH2:11][CH2:10]1.C(OC(=O)C)(=O)C.Cl[C:22](Cl)([F:27])[C:23]([O:25][CH3:26])=[O:24]>[Zn].[Cu]Cl.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]=[C:22]([F:27])[C:23]([O:25][CH3:26])=[O:24])[CH2:10][CH2:11]1
Reactant: COC(=O)C(F)(Cl)Cl
Reactant: O=CC1(c2ccc(F)cc2F)CC1
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(F)=CC1(c2ccc(F)cc2F)CC1
Yield: 38.8 %

Procedure:
The method of Example 1 was repeated using zinc powder (1 g), copper (I) chloride (0.12 g), molecular sieve 4A (1 g), tetrahydrofuran (18 ml), 1-(2,4-difluorophenyl)-1-formylcyclopropane (0.44 g), acetic anhydride (0.4 ml) and methyl dichlorofluoroacetate (0.62 g) to yield the title compound (0.24 g, 39%).
Reaction SMILES: C(OC(=O)[C:5](=[C:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:6]#[N:7])C.[C-:22]#[N:23].[K+]>CCO.O>[CH2:14]([N:11]1[CH2:10][CH2:9][C:8]([CH2:5][C:6]#[N:7])([C:22]#[N:23])[CH2:13][CH2:12]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: [C-]#N
Reactant: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC1(C#N)CCN(Cc2ccccc2)CC1
Reaction time: 24 h
Yield: 81.2 %

Procedure:
To a solution of (1-benzyl-piperidin-4-ylidene)-cyano-acetic acid ethyl ester (112.9 g, 0.40 mol) in EtOH (500 ml) and H2O (100 ml), potassium cyanide (64.6 g, 0.99 mol) is added at ambient temperature. The reaction mixture is stirred at 65 C.° for 24 h. After removal of EtOH, H2O is added to the residue. The waster phase is extracted with diethyl ether. The combined extracts are washed with H2O and brine, dried over sodium sulfate and evaporated down to give 77.7 g of 1-benzyl-4-cyanomethyl-piperidine-4-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]([C@@H:9]([NH2:11])[CH3:10])=[N:8][C:4]=2[CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]([C@@H:9]([NH:11][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[NH:23][CH:24]=[N:25]4)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2cc(F)ccc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2nc[nH]c12)c1nc2cc(F)ccc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
A mixture of (S)-1-(5-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 29 (379 mg, 1.4 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (340 mg, 1.4 mmol) and DIPEA (1.2 mL, 7.0 mmol) in n-butanol (7 mL) was stirred in a sealed vial for 18 h at 90° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was loaded into an Isolute® SCX-2 which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 161 (65 mg, 12%). LCMS: RT 3.34 min [M+H]+ 374.1. 1H NMR (DMSO, 400 MHz): δ 8.19-8.00 (2H, m), 7.92 (1H, s), 7.67-7.41 (6H, m), 7.06 (2H, d, J=7.13 Hz), 5.47 (1H, s), 1.56 (3H, d, J=6.83 Hz)
Reaction SMILES: O.[ClH:2].Cl.C([N:11](CC1C=CC=CC=1)[CH2:12][CH2:13][CH:14]1[CH2:18][N:17]([CH2:19][CH3:20])[C:16](=[NH:21])[N:15]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[ClH:2].[ClH:2].[NH2:11][CH2:12][CH2:13][CH:14]1[CH2:18][N:17]([CH2:19][CH3:20])[C:16](=[NH:21])[N:15]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCN1CC(CCN(Cc2ccccc2)Cc2ccccc2)N(c2ccccc2)C1=N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCN1CC(CCN)N(c2ccccc2)C1=N
Yield: 70 %

Procedure:
A solution of 10.0 g (0.023 mole) of 4-(2-dibenzylaminoethyl)-1-ethyl-2-imino-3-phenylimidazolidine dihydrochloride hydrate in 175 ml of ethanol was shaken for 7 hours in a Parr apparatus at 70° C. with palladium catalyst at 45 p.s.i. hydrogen. After filtering and concentrating the filtrate in vacuo, the solid residue was recrystallized from a 80/20% mixture of isopropanol-ethanol. The salt weighed 4.55 g (70% yield); m.p. 223°-224° C.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]1([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=3)[N:15]=[C:14]([N:23]3[CH2:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[S:26](=[O:34])[CH2:25][CH2:24]3)[N:13]=2)[CH2:10][O:9][CH2:8]1)=O.[OH-].[Na+]>C(O)C.O>[NH2:5][CH2:6][C:7]1([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=3)[N:15]=[C:14]([N:23]3[CH2:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[S:26](=[O:34])[CH2:25][CH2:24]3)[N:13]=2)[CH2:8][O:9][CH2:10]1
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(NC3(CNC(=O)C(F)(F)F)COC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(NC3(CN)COC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
To a stirred of 2,2,2-trifluoro-N-[(3-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]amino}oxetan-3-yl)methyl]acetamide (70 mg, 0.135 mmol) in ethanol (5 mL) was added an aqueous solution of sodium hydroxide (5 N, 1 mL). After being stirred at room temperature overnight, the resulting mixture was diluted with water (15 mL), and extracted with dichloromethane (15 mL×3). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 7 mg of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (s, 1 H), 7.83-7.78 (m, 2 H), 7.71-7.68 (m, 1 H), 7.61-7.54 (m, 3 H), 5.45 (d, 1 H), 5.15 (brs, 1 H), 4.81-4.74 (m, 5 H), 4.51 (brs, 3 H), 3.54 (brs, 2 H), 2.45 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([OH:18])[CH2:17]COCC3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[N:3]=1.[O:26]1CC(=O)[CH2:27]1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([OH:18])[CH2:17][O:26][CH2:27]3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[N:3]=1
Reactant: O=C1COC1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)CCOCC1)n2C
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)COC1)n2C

Procedure:
This compound was prepared in an analogous fashion to (S)-4-(2-chloro-9-methyl-6-(3-methylmorpholino)-9H-purin-8-yl)tetrahydro-2H-pyran-4-ol, using 3-oxetanone as the starting material. 1H NMR (CDCl3, 400 MHz) δ ppm 5.35 (broad s, 2H), 5.15 (t, J=6.9 Hz, 2H), 4.96 (d, J=7.2 Hz, 2H), 4.00 (dd, J=11.2, 3 Hz, 1H), 3.84 (s, 3H), 3.81 to 3.71 (m, 2H), 3.59 (td, J=11.6, 2.7 Hz, 1H), 3.47 (broad s, 1H), 1.39 (d, J=6.8 Hz, 3H); LC-MS m/z (method B2)=340/342 [M+H]+, RT=1.59 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]1[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:15]=[CH:16][N:17]=1)[CH2:6][CH2:5]2.C(N(CC)CC)C.[F:34][C:35]([F:52])([F:51])[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:43]([C:48](Cl)=[O:49])=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:14]2[C:13]([CH2:12][N:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:48]([C:43]5[C:42]([C:39]6[CH:40]=[CH:41][C:36]([C:35]([F:34])([F:51])[F:52])=[CH:37][CH:38]=6)=[CH:47][CH:46]=[CH:45][CH:44]=5)=[O:49])[CH:3]=4)[CH2:8]3)=[N:17][CH:16]=[N:15]2)=[CH:24][CH:23]=1
Reactant: COc1ccc(Cn2ncnc2CN2CCc3cc(N)ccc3C2)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2ncnc2CN2CCc3cc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)ccc3C2)cc1
Reaction time: 4 h
Yield: 97 %

Procedure:
The title product of Example 3 (0.38 g, 1.1 mmol) and triethylamine (0.17 mL, 1.2 mmol) were dissolved in methylene chloride (14 mL) and stirred at room temperature while a solution of 4'-trifluoromethylbiphenyl-2-carbonyl chloride (0.31 g, 1.1 mmol) in methylene chloride (40 mL) was added dropwise. After four hours, 10% aq sodium carbonate solution was added and the mixture was stirred for thirty minutes. The methylene chloride layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford the title product as a hard foam, 0.63 g, 97% yield. 1H NMR (CDCl3) δ 7.79 (s, 1), 7.72 (d, 1), 7.64 (d, 2), 7.58-7.34 (m, 6), 7.12 (d, 2), 7.01 (s, 1), 6.90-6.72 (m, 4), 5.38 (s, 2), 3.73 (s, 3), 3.69 (s, 2), 3.50 (s, 2), 2.79 (t, 2), 2.68 (t, 2). IR (KBr) 1668, 1615, 1599, 1567, 1536, 1514 cm-1. Mass spectrum: m/z: 598 (M+ -1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.C([O:42][C@@H:43]([CH3:47])[C:44](Cl)=[O:45])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH2:3][NH:2][C:44](=[O:45])[C@@H:43]([OH:42])[CH3:47])[CH:9]=[CH:8][CH:7]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)[C@H](C)O)c1
Reaction time: 4 h

Procedure:
A suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (100 mg, 0.2 mmol) in DCM (5 mL) and triethylamine (0.28 mL, 2 mmol) was treated with the (S)-2-acetoxypropionyl chloride (0.065 mL). After 4 h, the solvent was removed by evaporation and the residue was dissolved in methanol (10 mL) and then treated with solid potassium carbonate (277 mg, 2 mmol) and the mixture was stood at RT for 3 days. The mixture was concentrated under reduced pressure, and the residue was partitioned between 2M HCl and ethyl acetate. The organic solution was washed with more HCl, brine and dried (MgSO4). The filtrate was evaporated under reduced pressure to give a white solid (113 mg). The sample was dissolved in 1:1 MeOH-DMSO 2 mL and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was evaporated in vacuo to give the title compound (86 mg, 80%): LCMS (System A) RT=0.97 min, 100%, ES+ve m/z 535/537 (M+H)+; NMR δ (CD3OD) 7.27-7.15 (5H, m), 7.05 (1H, br d, J 7 Hz), 6.97 (1H, d, J 8 Hz), 6.89 (1H, d, J 4 Hz), 6.42 (1H, d, J 8 Hz), 5.47 (2H, s), 4.33 (2H, s), 4.12 (1H, q, J 7 Hz), 3.76 (3H, s), 1.30 (3H, d, J 7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.CN(C)C(=N)N(C)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:11][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Reactant: c1c[nH]cn1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1Cl)C(Cn1ccnc1)c1ccccc1
Yield: 12 %

Procedure:
A solution of 1-(2,4-dichlorophenyl)-2-phenylpropen-1-one (4 g), imidazole (1.36 g) and tetramethylguanidine (0.5 ml) in tetrahydrofuran (100 ml) was heated at reflux for 12 hours. The reaction mixture was cooled and concentrated under reduced pressure to yield a gum. The gum was dissolved in ethyl acetate, washed with distilled water, and acidified with 4N hydrochloric acid. The resulting aqueous phase was basified with sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was separated, washed with distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield an oil which was chromatographed on silica gel in methanol/dichloromethane (1:9) to yield 1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-phenylpropan-1-one (600 mg), which was treated with ethereal hydrogen chloride to yield the hydrochloride salt of 1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-phenylpropan-1-one, m.p. 110° C., (Found: C, 55.38; H, 4.37; N, 7.40; C18H15Cl3N2O.1/2H2O requires C, 55.34; H, 4.13; N, 7.17) having the formula: ##STR12##