Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>C(O)C>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]2[CH:17]=[CH:16][C:15]([S:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=3)=[C:14]([NH:13][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:19]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3ccc(Br)cc3)cc2N)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3ccc(Br)cc3)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 158a (37 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (26 mg, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.67-1.92 (m, 2H) 2.02 (s, 3H) 2.99 (t, J=7.54 Hz, 2H) 5.14 (s, 2H) 6.30 (d, J=6.99 Hz, 1H) 7.14 (d, J=8.46 Hz, 2H) 7.16-7.26 (m, 2H) 7.31-7.49 (m, 5H) 7.53-7.66 (m, 2H) 7.80 (d, J=8.46 Hz, 1H) 8.37 (d, J=6.99 Hz, 1H) 8.97 (d, J=8.82 Hz, 1H) 9.97 (s, 1H) 11.00 (s, 1H) 14.37 (s, 1H); MS (ESI+) m/z 615 (M+H)+.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH3:4].Cl.N1C=CC=CC=1.[NH2:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1[NH:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])=[CH:26][CH:25]=[CH:24][CH:23]=2>C(#N)C>[CH2:2]([C:1]1[N:29]([CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:18]=1)[CH2:3][CH3:4]
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Temperature: 25 °C

Procedure:
Trimethyl orthobutyrate (1.90 g, 12.7 mmol) and pyridine hydrochloride (0.13 g, 1.2 mmol) were added to a suspension of 1-[(3-aminoquinolin-4-yl)amino]-2-methylpropan-2-ol (prepared as described in Part A of Example 8, approximately 2.7 g, 11.5 mmol) in acetonitrile (60 mL). The reaction mixture was heated at reflux for 45 minutes with a Dean Stark trap, then was allowed to cool to room temperature and was concentrated under reduced pressure. The crude product was subjected to flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to yield a mixture of compounds that were combined and resubjected to the reaction conditions. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure to afford 1-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white solid that was used in the next step without purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.[OH:26]O>CO>[OH:26][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]2
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: OO
Solvent: CO
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (32 g, 88 mmol, Description 2) in methanol (320 ml) at room temperature under nitrogen, hydrogen peroxide (30 weight % in water, 17.90 ml, 175 mmol) was added and the resulting pale yellow solution stirred overnight. The mixture was then evaporated under reduced pressure and the residue partitioned between EtOAc (500 ml) and water (300 ml). Aqueous phase was back extracted with EtOAc (300 ml) and the combined organics were washed with brine (100 ml)/water (100 ml), dried over Na2SO4 and evaporated to dryness. The resulting pale yellow solid was triturated with Et2O (100 ml)/n-hexane (100 ml) and dried at high vacuum to give N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (20.85 g) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:14])=[C:8]([C:12]=1[CH3:13])[C:9]([OH:11])=[O:10])([O-:3])=[O:2].Cl[C:16]([O:18][CH2:19][CH3:20])=O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:14]=[C:16]([O:18][CH2:19][CH3:20])[O:10][C:9](=[O:11])[C:8]=2[C:12]=1[CH3:13])([O-:3])=[O:2]
Reactant: CCOC(=O)Cl
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1C(=O)O
Solvent: c1ccncc1
Product: CCOc1nc2ccc([N+](=O)[O-])c(C)c2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 4.0 g (20.4 mmoles) of 5-nitro-6-methyl-2-aminobenzoic acid in 50 mL of dry pyridine was cooled in an ice-water bath under inert atmosphere. Ethyl chloroformate (Aldrich), 10 mL (105 mmoles), was added dropwise over a 15 minute period. A mild exotherm was observed and a solid separated from solution immediately upon addition. The suspension was stirred at room temperature under inert atmosphere overnight. Approximately half the pyridine was removed in vacuo, and the residual mixture poured over ice. The precipitated solid was collected and air-dried. 4.0 g (79% yield) 6-nitro-5-methyl-2-ethoxy-3,1-benzoxazin-4-one was obtained. NMR (DMSO-d6): 1.37(t,3H,J=7.2 Hz), 2.71(s,3H), 4.50(q,2H,J=7.2 Hz), 7.40(d,1H, J=9.0 Hz), 8.19(d,1H,J=9.0 Hz). IR(nujol): 1765 cm-1 (lactone carbonyl). MS(m/z): 250(M+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1C(C)O.[C:14]1(C)C(S(O)(=O)=O)=CC=C[CH:19]=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:14]=[CH2:19])=[CH:9][CH:10]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CC(O)c1ccccc1CCCBr
Solvent: Cc1ccccc1
Product: C=Cc1ccc(CCCBr)cc1

Procedure:
The product from Example 2 is used as a stating material in this procedure. The resulting product from Example 2 was diluted in 200 mL of toluene. Next, 0.125 g of toluensulfonic acid was added to the reaction mixture. The reaction mixture was refluxed under argon atmosphere for 44 hours. The mixture was then washed with 50 mL of water and the solvent was removed under vacuum. The resulting product was then purified by silica gel chromatography with the use of 90% hexane and 10% ethyl acetate. The resulting product was recovered as the solvent was removed under vacuum.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(NC1C=CC(S([N:27]=[N+:28]=[N-])(=O)=O)=CC=1)=O.C1CCN2C(=NCCC2)CC1>CC#N>[N+:27](=[C:9](/[CH:8]=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:10]([O:12][CH3:13])=[O:11])=[N-:28]
Reactant: COC(=O)C/C=C/c1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(/C=C/c1ccccc1)=[N+]=[N-]
Temperature: 25 °C
Yield: 80.1 %

Procedure:
Methyl (E)-2-diazo-4-phenyl-3-butenoate (9) was prepared according to the procedure described in Davies, et al., J. Org. Chem., 56:3817 (1997) (“Davies II”), which is hereby incorporated by reference). The scheme is set forth in FIG. 7B. Briefly, to a stirred solution of methyl trans-4-phenylbut-3-enoate (1.0 g, 5.68 mmol) and p-ABSA (1.64 g, 6.82 mmol) in CH3CN (150 mL) cooled to 0° C., was added DBU (0.95 g, 6.25 mmol) in one portion. The reaction mixture was allowed to warm to room temperature over 7 h then quenched with saturated ammonium chloride (NH4Cl). The aqueous layer was extracted with diethyl ether, and the combined organic layers were washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure, and the residue was triturated with a solution of pentane/diethyl:ether (1:1). The solid was filtered off, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO2, pentane/diethyl:ether (15:1)) to give methyl (E)-2-diazo-4-phenyl-3-butenoate (9) (0.92 g, 80% yield) as an orange oil, which was stored neat at −10° C. until ready for use. The spectroscopic data are consistent with previously reported data ((Davies II, which is hereby incorporated by reference).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.CC[Mg+].[Br-].C(OCC)C.[CH:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1)=[O:19]>C1COCC1>[CH2:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([CH:18]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[OH:19])[CH2:21][CH2:22]1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Brc1ccc(I)cc1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC(C(O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 1-bromo-4-iodobenzene (17.16 g, 60.7 mmol) in THF (130 ml) was immersed in a dry ice-methanol bath. EtMgBr 3M in diethylether (27.0 ml, 81 mmol) was added slowly via syringe at −44° C. to −40° C. (exothermic reaction, grey precipitation!). The reaction mixture was allowed to warm up to −10° C. and after 2 hrs 1-bromo-4-iodobenzene was gone. Then a solution of benzyl 4-formylpiperidine-1-carboxylate (10 g, 40.4 mmol) in THF (30 ml) was added slowly below −65° C. The reaction was allowed to warm up to room temperature and stirred for 14 hrs. The reaction mixture was quenched with saturated aqueous ammonia chloride solution and diluted with ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude material which was purified by automated column chromatography (normal phase, ethyl acetate/n-heptane) to obtain the title compound as colorless oil.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:44]=[C:39]1[NH:38][CH2:43][CH2:42][N:41]([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[CH2:11]2)=[O:27])[CH2:40]1
Reactant: O=C1CNCCN1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(C(F)(F)F)cc3)C2)CCN1

Procedure:
80 mg (0.16 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 1.7 ml of DMF, and 47 mg (0.47 mmol) of piperazin-2-one and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 39 mg (52% of theory)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:16](OCC)=[O:17]>>[CH:16]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: NCCCNC(=O)OCc1ccccc1
Reactant: CCOC=O
Product: O=CNCCCNC(=O)OCc1ccccc1
Yield: 99 %

Procedure:
Benzyl 3-aminopropylcarbamate 12 (8.00 g, 36.0 mmol) was dissolved in 250 mL of ethyl formate. The solution was refluxed for 4 h. Following complete conversion of the amine, the solution was concentrated to dryness in a rotary evaporator to obtain the formamide as a colorless oil (8.90 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O.CCOCC>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][N:26]=[N+:27]=[N-:28])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H]3C[C@H]3N2C(=O)OC(C)(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@H](CN=[N+]=[N-])C[C@H]2C[C@H]21
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of (1R,3S,5R)-3-(toluene-4-sulfonyloxymethyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (0.400 g, 1.08 mmol) and NaN3 (0.420 g, 6.47 mmol) in dry DMSO (8 mL) was stirred at 65° C. overnight. After cooling, the mixture was diluted with Et2O and washed with water (×3) and brine (×2). The organics were dried (phase separator) and concentrated in vaccuo to give the title compound as a colorless oil. MS (LC-MS): 239.0 [M+H]+; tR (HPLC conditions k): 3.78 min. The material thus obtained was used in the next step without further purification.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])C.[F:17][C:18]([F:23])([F:22])[CH2:19][NH:20]N>C(O)(=O)C.C(O)CCC>[F:17][C:18]([F:23])([F:22])[CH2:19][N:20]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[N:5][CH:4]=[N:2]1
Reactant: CN(C)C=NC(=O)c1ccccc1[N+](=O)[O-]
Reactant: NNCC(F)(F)F
Solvent: CCCCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1-c1ncnn1CC(F)(F)F

Procedure:
N-[(Dimethylamino)methylene]-2-nitrobenzamide (1.0 g, 4.5 mmol) in acetic acid (25 mL) and n-butanol (15 mL) was treated with 70% aqueous 1,1,1-trifluoroethylhydrazine (1 mL, 11.3 mmol), and heated to reflux for 2 hours, at which time the volume was reduced by ˜25 mL by distillation. The remaining solvent was removed in vacuo, and the residue chromatographed on silica eluting with 3:1-1:1 hexane:ethyl acetate to afford 1-(2,2,2-trifluoroethyl)-5-(2-nitrophenyl)-1,2,4-triazole, which was reduced as in Example 64 to give crude 1-(2,2,2-trifluoroethyl)-5-(2-aminophenyl)-1,2,4-triazole (430 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:27][CH:28]=2)=[CH:18][CH:17]=1)(=O)=O>>[N:1]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:27][CH:28]=3)=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: C(=C/c1nc(COc2ccc(CCCCCn3ccnc3)cc2)co1)\c1ccccc1
Yield: 66 %

Procedure:
In substantially the same manner as in Working Example 8, imidazole was allowed to react with 5-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]pentyl methanesulfonate to give 4-[4-[5-(1-imidazolyl)pentyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 66%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 101-102° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(CCOCc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (1.0 g) in N,N-dimethylformamide (25 mL) was added 55% sodium hydride (0.26 g) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added benzyl bromide (0.77 mL) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=20/1) to give 1-[2-(benzyloxy)ethyl]-4-bromobenzene (1.35 g). The title compound was prepared in a similar manner to that described in Step 2 of Reference Example 46 using this material instead of 1-bromo-2-fluoro-4-methoxybenzene.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]2[C:27]([CH2:28][NH:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=4[Cl:42])[CH:33]=[N:32][N:31]=3)=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[N:18]1([C:22]2[C:27]([CH2:28][NH:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=4[Cl:42])[CH:33]=[N:32][N:31]=3)=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:19][CH2:20][CH2:21][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ncccc2CNc2nncn2-c2cccc(Cl)c2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(-n2cnnc2NCc2cccnc2N2CCCNCC2)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (15 mL) was added to a solution of Example 112C (2.0 g, 3.86 mmol) in dichloromethane (75 mL) at 0° C. 5 minuted later, the ice bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane. The organic was washed with saturated sodium bicarbonate and the pH was adjusted to 9. The layers were separated and the aqueous layer was extracted with dichloromathane. The combined organic layer was washed with brine, dried over magnium sulfate, filtered and concentrated to yield the title compound that was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:34](=[O:37])[CH:35]=[CH2:36])[CH:11]([C:15]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:32])[C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[CH:20][CH:21]=2)[N:16]=1)[CH:12]([CH3:14])[CH3:13])(C)(C)C.C(Cl)(=O)C=C.C(OC(=O)NCCNC(C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C)(C)(C)C.CCN(CC)CC>C(Cl)Cl>[CH2:25]([N:24]1[C:23](=[O:32])[C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[CH:20][CH:21]=2)[N:16]=[C:15]1[CH:11]([N:10]1[C:34](=[O:37])[CH2:35][CH2:36][NH:7][CH2:8][CH2:9]1)[CH:12]([CH3:13])[CH3:14])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C=CC(=O)N(CCNC(=O)OC(C)(C)C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Agent: C=CC(=O)Cl
Agent: CC(C)C(NCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-{Acryloyl-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-amino}-ethyl)-carbamic acid tert-butyl ester: Acryloyl chloride (126 μL, 1.6 mmol) was added to {2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-ethyl}-carbamic acid tert-butyl ester (500 mg, 1.03 mmol) and Et3N (216 μL, 0.15 mmol) in CH2Cl2 (10 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (10 mL), washed with brine, dried and concentrated under vacuum. Purification by flash chromatography on silica gel (10% EtOAc/hexane) gave the title compound (310 mg) as a white solid: MS (ES) m/e 539.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:5][CH:4]1[CH2:6][OH:7].C(S([C:12]1[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH:22]2[CH:26]3[CH2:27][CH2:28][CH:23]2[CH2:24][CH2:25]3)=[O:18])=[CH:15][N:16]=1)=O)C>O1CCCC1>[O:5]1[CH:4]([CH2:6][O:7][C:12]2[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH:22]3[CH:26]4[CH2:25][CH2:24][CH:23]3[CH2:28][CH2:27]4)=[O:18])=[CH:15][N:16]=2)[CH2:3]1
Reactant: OCC1CO1
Reactant: CCS(=O)c1ncc(C(=O)NCCC2C3CCC2CC3)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCC1C2CCC1CC2)c1cnc(OCC2CO2)s1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
This example illustrates the process of the invention for preparing 1,2-epoxy-3-(5-substituted aminocarbonylthiazole-2-yloxy)propane. In this example 0.0525 mole of sodium hydride in a 50% mineral oil mixture is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, then cooled to -30° C and 0.055 mole of glycidol is added dropwise. The mixture is allowed to warm to -5° C and stirred for 10 minutes and then recooled to -30° C. A solution of 0.05 mole of 2-ethylsulfinyl-5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazole in 100 ml. of anhydrous tetrahydrofuran is added dropwise and the resulting mixture allowed to warm to 0° C. Additional solvent is added as needed to facilitate stirring. The mixture is maintained for 30 minutes at 0° C and then poured into 500 ml. of ethyl acetate, extracted with 100 ml. of water, and then with 100 ml. of aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording oily residue which is then further purified by chromatography on silica gel eluting with 40% ethyl acetate-60% hexane, by vol., affording 1,2-epoxy-3-(5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazol-2-yloxy)propane.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:16]=2[C:15](=[O:23])[N:14]([C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH3:25])[C@@H:13]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[C:12]1=[O:40])(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:13]2[C:12](=[O:40])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:41])=[O:5])[C:17]3[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:16]=3[C:15](=[O:23])[N:14]2[C@@H:24]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[CH3:25])=[CH:34][CH:35]=1
Reactant: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(I)ccc2N(CCCCC(=O)OC(C)(C)C)C(=O)[C@@H]1c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(I)ccc2N(CCCCC(=O)O)C(=O)[C@@H]1c1ccc(Cl)cc1
Yield: 96.5 %

Procedure:
5-{(3S)-3-(4-Chloro-phenyl)-4-[(R)-1-(4-chloro-phenyl)-ethyl]-7-iodo-2,5-dioxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-pentanoic acid tert-butyl ester (1.0 g, 1.4 mmol) was dissolved in a solution of 20% TFA [10 mL] in dichloromethane at room temperature for 2 hours. The reaction was concentrated and the product was purified by chromatography (hexane: EtOAc 1:1) to give the title compound (0.88 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J=2.3 Hz. 1H), 7.62–7.56 (m, 3H), 7.39 (d, J=8.6 Hz, 2H), 7.00 (d, J=8.6 Hz, 2H), 6.92 (d, J=8.6 Hz, 1H), 6.58–6.56 (m, 2H), 6.21–6.14 (m, 1H), 5.27 (s, 1H), 4.24–4.15 (m, 1H), 3.69–3.61 (m, 1H), 1.80 (t, J=7.2 Hz, 2H), 1.63 (d, J=7.2 Hz, 3H), 1.56–1.21 (m, 4H). Mass spectrum (LCMS, ESI pos.): Calcd for C28H25Cl2IN2O4: 650.02; found 650.8(M+H).
Reaction SMILES: [CH2:1]([C:10]1[O:14][C:13]([C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17](O)=O)=[N:12][N:11]=1)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1>C1C=CC=CC=1.C(O)C>[CH2:1]([C:10]1[O:14][C:13]([C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[CH3:17])=[N:12][N:11]=1)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1Cc1nnc(-c2ccccc2C(=O)O)o1
Solvent: c1ccccc1
Solvent: CCO
Product: COc1ccccc1Cc1nnc(-c2ccccc2C)o1

Procedure:
2-[5-(2-Anisyl)-1,3,4-oxadiazole-2-yl] benzoic acid, M.P. 157°-160° (benzene/ethanol) wt., 1.7 g (17.9%). (Found: C, 66.22, 65.42; H, 4.46, 4.46; N, 9.68, 9.97. C16H12N2O4 requires C, 64.86; H, 4.08; N, 9.46.)