Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:42]=[C:43]([Cl:45])[CH:44]=1)[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]3[N:32]([C:33]([CH3:36])=[N:34][N:35]=3)[C:27]=2[CH:26]=[C:25]1[C:37]1[NH:41][N:40]=[CH:39][CH:38]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:48]I>CN(C=O)C>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:42]=[C:43]([Cl:45])[CH:44]=1)[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]3[N:32]([C:33]([CH3:36])=[N:34][N:35]=3)[C:27]=2[CH:26]=[C:25]1[C:37]1[CH:38]=[CH:39][N:40]([CH3:48])[N:41]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CI
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3cc(Cl)cc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c3)n12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(cc(-c4ccn(C)n4)n3Cc3cc(Cl)cc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c3)n12
Reaction time: 0.17 h

Procedure:
6-[3-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl]-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.20 g, 0.22 mmol, from Step 4) in DMF (4.7 mL) was treated with NaH (60% in mineral oil, 27 mg, 0.66 mmol). After 10 minutes, MeI (41 μL, 0.66 mmol, Aldrich) was added to the reaction mixture. After 10 minutes, the reaction was quenched by the addition of water, and the product was purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (50 mg, 30%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:11][C:8]2=[N:9][CH:10]=1)(=[O:4])=[O:3].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.[H-].[Na+]>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=3)[C:8]2=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: Fc1ccc(CBr)cc1
Reactant: CS(=O)(=O)c1cnc2[nH]c(-c3ccccn3)cc2c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ccccn1)n2Cc1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
To a solution of the compound obtained in Example 5 (4) (2.3 mg) in N,N-dimethylformamide (0.5 ml), 60% sodium hydride. (0.5 mg) was added at 0° C. and the mixture was stirred at the same temperature for 15 minutes. p-Fluorobenzyl bromide. (2.4 mg) was then added thereto at 0° C. and the mixture was stirred at 15 to 30° C. for 1 hour. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with toluene, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (chloroform:methanol=100:1) to obtain 1.7 mg of the desired product as a white powder.
Reaction SMILES: [S:1](S([O-])=O)([O-:4])(=[O:3])=[O:2].[Na+].[Na+].[NH2:10][C:11]1[N:16]=[CH:15][C:14]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:13]2[N:12]=1>O.C(O)C>[NH2:10][C:11]1[NH:16][CH:15]([S:1]([OH:4])(=[O:3])=[O:2])[C:14]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:13]2[N:12]=1
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CCCc1nc(C)c2cnc(N)nn12
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1nc(C)c2n1N=C(N)NC2S(=O)(=O)O

Procedure:
Sodium metabisulphite (1.5 g.) in water (45 ml.) was added to 2-amino-5-methyl-7-propylimidazo[5,1-f]-as-triazine (Example 4) (1.9 g.) in ethanol (20 ml.). The solid was collected and dried and had m.p. 232°-234°.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][CH2:39][N:40]5[CH:44]=[N:43][N:42]=[CH:41]5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][CH2:39][N:40]5[CH:41]=[N:42][N:43]=[CH:44]5)=[O:54])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCCn4cnnc4)cc2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)CCn4cnnc4)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylthio)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (1.0 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.43 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:20→1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 157) (0.90 g) as yellow amorphous.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:27]([NH:39][C:40](=[O:53])[C:41]3[CH:46]=[CH:45][C:44]([C:47]4[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=4)=[CH:43][CH:42]=3)[CH:26]=2)=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[OH:18][CH2:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:27]([NH:39][C:40](=[O:53])[C:41]3[CH:42]=[CH:43][C:44]([C:47]4[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=4)=[CH:45][CH:46]=3)[CH:26]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)s2)cc1NC(=O)c1ccc(-c2cccnc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(CO)s2)cc1NC(=O)c1ccc(-c2cccnc2)cc1
Yield: 90 %

Procedure:
Following the same procedure as described in Example 20, step 5 (scheme 20) but substituting compound 189 for compound 198, title compound 199 was obtained in 90% yield [after column chromatography (eluent: 25% AcOEt in DCM)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C@H:10]2[CH2:23][NH:24][C:25](=[O:29])[CH2:26][O:27][CH3:28])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.C(O)C>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:23][NH:24][C:25](=[O:29])[CH2:26][O:27][CH3:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COCC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCO
Product: COCC(=O)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 181 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-{[(methoxyacetyl)amino]methyl}-1,4-oxazepane-4-carboxylate (161 mg) in ethanol (1 ml) was added 14.0 M hydrogen chloride-ethanol solution (2 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from ethanol to give the title compound (125 mg) as colorless crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].C1[C:8]2([CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9]2)[CH2:7][O:6]1>>[OH:6][CH2:7][C:8]1([CH2:9][O:4][CH2:3][CH2:2][Cl:1])[CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10]1
Reactant: OCCCl
Reactant: C1COCCOCC2(COCCOCCN1)COC2
Product: OCC1(COCCCl)COCCOCCNCCOCCO1

Procedure:
The oxetane ring in 2,6,9,15,18-pentaoxa-12-azaspiro[3.15]nonadecane was shown to add hydroxylic compounds by acid-catalyzed reaction with 2-chloroethanol to give 1-hydroxymethyl-1-(4-chloro-2-oxabutyl)-2,5,11,14-tetraoxa-8-azacyclopentadecane. ##EQU13##
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([C:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:28]=[CH:29][N:30]=[CH:31][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:20][N:21]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:28]=[CH:29][N:30]=[CH:31][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1=C(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CCNC1
Agent: [Pd]
Solvent: CO
Product: c1cc2c3cnc(Nc4ccc(C5CCNCC5)cn4)nc3n(C3CCCC3)c2cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of compound 412 (90 mg, 0.22 mmol) in methanol (5 mL) was added Pd/C (10% wt, dry basis) (50 mg). The reaction was stirred at room temperature with H2 ballon for 3 hours. Insolubles were removed by filtration. The filtrate was purified using prep-HPLC to give compound 413 as a yellow solid (30 mg, 33%). 1H NMR (500 MHz, DMSO-d6) δ ppm 10.98 (1 H, br. s.), 9.64 (1 H, s), 9.42 (1 H, s), 8.83 (1 H, dd, J=3.5, 1.1 Hz), 8.71 (1 H, d, J=6.1 Hz), 8.55-8.68 (2 H, m), 8.30 (1 H, d, J=2.7 Hz), 8.17 (1 H, d, J=8.6 Hz), 7.85 (1 H, dd, J=8.8, 2.4 Hz), 5.41 (1 H, dq, J=8.9, 8.8 Hz), 3.43 (2 H, dd, J=10.4, 2.3 Hz), 2.96 (3 H, tt, J=12.1, 3.7 Hz), 2.42 (2 H, m), 2.00-2.08 (4 H, m), 1.68-1.92 (2 H, m); LCMS-ESI (POS), M/Z, M+1: Found 414.2, Calculated 414.2.
Reaction SMILES: Br[CH:2]([CH3:11])/[C:3](/OC)=[CH:4]\[C:5]([O:7][CH3:8])=[O:6].[C:12]([NH2:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH3:11][C:2]1[O:19][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:20][C:3]=1[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)/C=C(/OC)C(C)Br
Reactant: NC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C
Temperature: 120 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A 200-ml 4-necked flask equipped with a mechanical stirrer, a thermometer, a distillation head, a vacuum controller, an argon inlet and an oil bath was charged with 24.7 g of crude methyl rac-(E)-4-bromo-3-methoxy-pent-2-enoate (ca. 0.107 mol), 19.91 g of benzamide (0.161 mol) and 57 ml of toluene. The orange suspension was stirred and heated with an oil bath at 120° C. At a still temperature of 111° C. low boiling componentes started to distill. The head temperature reached 103° C. after ca. 1 h and was 65° C. after 6 h. After 9 h the oil bath was removed and the reaction mixture stirred over night at rt. Thereafter the toluene was removed at 60° C. bath temperature and a pressure between 300 and 70 mbar. After cooling to rt, 80 ml of methanol and 0.60 g of p-toluenesulfonic acid monohydrate were added and the brown solution stirred at reflux (ca. 73° C.) for 2 h. Subsequently 2.5 g of charcoal and 50 ml of methanol were added, the mixture was stirred for 30 min, filtered with suction through Dicalite Speedex and rotary evaporated to dryness (50° C., 8 mbar, 30 min). The orange semi-solid residue was treated under argon with 250 ml of toluene and 55 ml of sat. aqueous sodium bicarbonate solution. The resulting suspension was stirred in an ice bath for 0.5 h, the precipitated benzamide was filtered off with suction and the filter cake was washed three times with 50 ml portions, a total of 150 ml of ice cold toluene and with little water. The combined aqueous phases (pH=8)were extracted in a separatory funnel with 80 ml of toluene. Thereafter the combined organic phases were washed twice with 50 ml, a total of 100 ml of deionized water, dried (Na2SO4) and rotary evaporated (50° C., 10 mbar, 1 h) to give 21.8 g of crude Methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate (theor. amount 24.7 g) as a red-brown oil, which can be used without purification in subsequent steps.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>O1CCCC1>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:3]1([CH2:4][N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)[O:10][C:19](=[O:20])[NH:1][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: O=C1NCC(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1

Procedure:
A solution of the amine (A) (0.1 g, 0.35 mmole) and 1,1'-carbonyldiimidazole (0.056 g, 0.35 mmole) in tetrahydrofuran (5 ml) was stirred at room temperature for five hours. The solvent was then evaporated and the residue was dissolved in ethyl acetate (20 ml). This solution was washed three times with water (300 ml, total), dried (MgSO4), evaporated and the residue triturated with a mixture of 60°-80° C. petrol:ether to give, as a white solid, the title compound, 0.074 g (68%), m.p. 223° C.
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].[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1([CH3:44])[CH3:43])=[O:36])([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([CH2:18][C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)[CH2:39][C:38]1([CH3:44])[CH3:43])=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)OC(C)(C)C)C(C)(C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (530 mg, 1.35 mmol), 2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester (350 mg, 1.63 mmol) and molecular sieves (4 Å, powdered, 2.5 g) in DCE (30 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (427 mg, 2.02 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; 100:0 to 95:5 to 90:10) to give 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester. TFA (3 mL) was added to a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH before the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 98:2 to 95:5 to 90:10 to 80:20) to afford 552 as a cream solid (144 mg, 22%). LCMS (Method I): RT=2.56 min, M+H+=490. 1H NMR (CDCl3, 400 MHz) δ 8.02 (m, 1 H); 7.75 (m, 1 H); 7.29 (m, 2 H); 4.35 (m, 4 H); 3.92-3.83 (m, 7 H); 3.70 (s, 2 H); 3.36 (q, J=7.5 Hz, 2 H); 2.97 (m, 2 H); 2.47 (m, 2 H); 2.28 (s, 2 H); 1.49-1.42 (m, 3 H) and 1.19 (s, 6 H)
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[C@H:20]([N:24]1[CH:28]=[C:27]([CH2:29][N:30]2C(=O)C3=CC=CC=C3C2=O)[N:26]=[C:25]1[C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:30][CH2:29][C:27]1[N:26]=[C:25]([C:41]2[CH:42]=[CH:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[N:24]([C@@H:20]([C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=3)[N:10]=2)[CH:21]([CH3:23])[CH3:22])[CH:28]=1
Reactant: Cc1ccc(-c2nc(CN3C(=O)c4ccccc4C3=O)cn2[C@@H](c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc(CN)cn2[C@@H](c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.2 %

Procedure:
To N-{1-[(R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-2-p-tolyl-1H-imidazol-4-ylmethyl}-phthalimide (3.50 g, 5.5 mMol) in EtOH (100 mL) was added hydrazine monohydrate (1.1 mL, 22.7 mMol). The reaction was stirred at RT for 72 h, filtered through a pad of Celite® to remove the insoluble precipitate, rinsed with EtOH and evaporated to dryness. Purification by flash chromatography on silica gel [5–10% (5% NH4OH in MeOH)/CH2Cl2] gave the title compound (2.71 g, 96%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=8.6 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.40–7.51 (m, 6H), 7.15–7.22 (m, 3H), 6.43 (d, J=7.1 Hz, 2H), 5.78 (d, J=16.3 Hz, 1H), 4.84 (d, J=10.5 Hz, 1H), 3.87 (d, J=16.3 Hz, 1H), 3.83 (2d, 2H), 3.00 (m, 1H), 2.60 (br s, 2H), 2.54 (s, 3H), 0.90 (d, J=6.7 Hz, 3H), 0.31 (d, J=6.7 Hz, 3H); MS (ES) m/e 512.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:14])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([N:31]1[C:36](=[O:37])[C:35]([CH3:38])=[CH:34][NH:33][C:32]1=[O:39])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:8][CH2:9][C@@H:10]([CH2:11][N:33]1[CH:34]=[C:35]([CH3:38])[C:36](=[O:37])[N:31]([C:23](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:32]1=[O:39])[C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c[nH]c(=O)n(C(=O)c2ccccc2)c1=O
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)COCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cn(C[C@H](COCc2ccccc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a cold (ice/water bath) solution of (2R,3R)-2-((benzyloxy)methyl)-3-(tert-butyldimethylsiloxy)butan-1-ol (4) (W.-H. Ham et al. J. Org. Chem. 2000, 65, 8372-8374) 1.5 g, 4.6 mmol), 3-benzoylthymine (1.5 g, 6.5 mmol) and triphenylphosphine (1.71 g, 6.5 mmol) in 50 ml of anhydrous THF was added dropwise via syringe with stirring (1.26 ml, 6.5 mmol) of diisopropylazodicarboxylate. The reaction was removed from the bath and stirred at room temperature for 2 hrs and then concentrated. The reaction was diluted with ether (50 ml) and hexane (50 ml) to precipitate some of triphenylphosphine oxide and the DIPADC by-product. The solids were filtered off and the filtrate concentrated. The resultant crude product, which still contained some Ph3PO, was chromatographed on silica eluting with 20% ethyl acetate in hexane. Concentration of the pure product fractions afforded 2.0 g (81%) of 5 as a colorless viscous srup. 1H NMR (CDCl3): δ 7.85 (d, J=8.4 Hz, 2H), 7.58 (t, J=7.5 Hz, 1H), 7.42 (t, J=7.8 Hz, 2H), 7.35-7.25 (m, 5H), 7.06 (d, J=1.2 Hz, 1H), 4.42 (s, 2H), 3.98 (m, 2H), 3.61 (m, 1H), 3.46 (d, J=5.7 Hz, 2H), 2.08 (m, 1H), 1.83 (s, 3H), 1.16 (d, J=6.6 Hz, 3H), 0.84 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:7][C:8]([C:10]1[C:14]([C:15]([O:17]CC)=[O:16])=[C:13]([CH3:20])[O:12][N:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.C(O)C>[C:3]([NH:7][C:8]([C:10]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:20])[O:12][N:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(=O)c1c(C(=O)NC(C)(C)C)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1onc(C(=O)NC(C)(C)C)c1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
At from 5° to 10° C. and under a nitrogen blanket, 1.0 g (25.0 mmol) of sodium hydroxide in 50 ml of water was dripped into a solution of 5.4 g (21.3 mmol) of 4-ethoxycarbonyl-5-methyl-isoxazole-3-carboxylic acid-tert-butylamide in 100 ml of ethanol, and the mixture was stirred for 12 hours at room temperature. The solution was evaporated down, the residue was taken up in 150 ml of water, the pH was adjusted to 8-9, and the mixture was extracted twice, each time with 100 ml of diethylether. The aqueous phase was then acidified to a pH of 2 with 6N HCl, followed by extraction four times, each time with 200 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and the solvent was stripped off under reduced pressure. Yield: 95%; yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17](O)[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].C1CCC(N=C=NC2CCCCC2)CC1.[SH:45][C:46]1[S:47][CH2:48][CH2:49][N:50]=1>C(Cl)Cl>[OH:25][CH:23]1[CH2:24][CH:19]2[C:20]([CH3:26])([CH:15]3[CH:16]([CH2:17][CH2:18]2)[CH:11]2[C:12]([CH3:29])([CH:8]([CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([N:50]4[CH2:49][CH2:48][S:47][C:46]4=[S:45])=[O:6])[CH2:9][CH2:10]2)[CH:13]([OH:28])[CH2:14]3)[CH2:21][CH2:22]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: SC1=NCCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(CCC(=O)N1CCSC1=S)C1CCC2C3CCC4CC(O)CCC4(C)C3CC(O)C12C
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.3 %

Procedure:
To a vigorously stirred solution of cholic acid (1 g, 2.6 mmol) in CH2Cl2 (60 mL) was added DCC (684 mg, 3.6 mmol), 2-mercaptothiazoline (354 mg, 3 mmol), and catalytic amount (40 mg) of N,N-dimethyl amino pyridine (DMAP). The reaction mixture was stirred for 24 h at room temperature at which time the reaction mixture was transferred to a separate-funnel and sequentially washed with 0.5N NaOH solution (100 mL×2), and 0.1N HCl (100 mL×2). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide pure yellow solid 2 (1.07 g, 82%). 1H NMR (CDCl3) δ 0.68 (s, 3H), 0.90 (s, 3H), 0.98 (d, 3H), 1.10-1.95 (m, 23H), 3.25-3.35 (m, 4H), 3.53-3.67 (m, 1H), 3.98 (s, 1H), 4.57 (t, 2H); 13C NMR (CDCl3) δ12.73, 17.49, 23.16, 23.76, 26.17, 27.21, 27.63, 28.33, 28.60, 30.40, 30.74, 33.52, 34.11, 35.32, 35.48, 35.87, 36.00, 36.40, 42.08, 46.52, 47.44, 48.09, 53.59, 56.16, 71.53, 72.99, 175.35, 201.52. HRMS (Positive ion FAB) Calcd for C27H44N3O2 [M+H]+ m/z 494.2763. Found: [M+H]+ m/z 494.2744.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:1][C:13]1[S:9][C:10]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1csc(-c2cccs2)c1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Brc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
N-Bromosuccinimide (NBS, 1.12 g, 6.3 mmol) was added in small portions to a stirred solution of 1.0 g {6.01 mmol} of 2,2'-bithiophene in 10 ml of glacial acetic acid and 10 ml of chloroform. After stirring for 1 h at room temperature, the mixture was poured into ice-water and extracted into chloroform (75 ml). The organic layer was washed with aqueous sodium bicarbonate solution, water, and then dried over magnesium sulfate and evaporated. The residue was subjected to flash chromatography on silica gel using hexane to give 1.3 g (88%) of a light green solid, m.p. 55-56° C.