Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[NH:2]1.C(N(CC)CC)C.[CH2:20]([O:27][C:28](ON1C(=O)CCC1=O)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[N:1]1([C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH2:5][CH2:4][CH:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[NH:2]1
Reactant: CC(C)(C)OC(=O)C1CCNN1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 110.9 %

Procedure:
At 0° C., to a 50 mL round bottomed flask charged with 1,1-dimethylethyl 3-pyrazolidinecarboxylate (0.054 g, 0.259 mmol) and stirrer in dichloromethane (DCM) (3 mL), was added triethylamine (0.079 mL, 0.569 mmol). After a couple of minutes, N-(benzyloxycarbonyloxy)succinimide (CBz-OSu) (0.064 g, 0.259 mmol) in dichloromethane (DCM) (1.5 mL) was added dropwise. The reaction mixture stirred at 0° C. for one hour, then warmed to r.t. After 2 hr at r.t., the solvent was evaporated and the residue was dissolved in EtOAc (30 mL), washed with water (15 mL×2), sat. NaHCO3 (15 ml), brine (15 mL), dried over Na2SO4 and concentrated to afford the crude product as a colorless gum (88 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=1>ClCCl>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:21])=[C:18]([C:25]([F:26])([F:27])[F:28])[CH:17]=1
Reactant: O=C1CNCCN1
Reactant: O=C(Cl)c1ccc(Cl)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)c2ccc(Cl)cc2C(F)(F)F)CCN1
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.5 g, 4.99 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (30 mL), and to this was added triethylamine (0.835 mL, 5.99 mmol). The solution was then cooled to 0° C. before 4-chloro-2-(trifluoromethyl)benzoyl chloride (1.335 g, 5.49 mmol, commercially available from e.g. 3B Scientific or APAC) in dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then dissolved in DCM (20 mL) and the solution was washed with water (10 mL), a saturated solution of sodium bicarbonate (10 mL) and brine (10 mL). The organic phase was then dried over anhydrous sodium sulphate, and the solid sodium sulphate was then filtered off. The solvent was then evaporated in vacuo, and the remaining solid was stirred in hexane, at 55° C., for 30 minutes. The solid was then filtered off to yield the desired product in 1.445 g.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH:5]=O.O.[NH2:17]N>C(O)C>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[N:2][NH:17][CH:5]=1
Reactant: NN
Reactant: COc1ccccc1C(C=O)=CN(C)C
Solvent: CCO
Solvent: O
Product: COc1ccccc1-c1cn[nH]c1
Yield: 68 %

Procedure:
A solution of 3-dimethylamino-2-(2-methoxyphenyl)propenal (4.68 g, 22.8 mmol) and hydrazine hydrate (6.7 ml) in ethanol (100 ml) is heated at reflux for 30 minutes. The solvent is removed in vacuo and the residue is chromatographed (silica gel, dichloromethane/ethanol 95:5) to give 2.69 g of 4-(2-methoxyphenyl)pyrazole (68%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4]([CH3:6])=O.C(OP([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(OCC)=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4]([CH3:6])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COC(OC)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C=C(C)C(OC)OC
Reaction time: 24 h

Procedure:
A mixture of 50 mmol of 1,1-dimethoxyacetone and 60 mmol of ethyl 2-(diethoxyphosphoryl)acetate is added in the course of 1 hour to a suspension of 125 mmol of potassium carbonate in 10 ml of water with vigorous stirring and with temperature maintained at between 20° and 30° C. When the addition is complete, stirring is continued for 24 hours at room temperature and the insoluble matter is then removed by filtration and washed with diethyl ether. The organic phase is separated and washed with saturated sodium chloride solution to neutrality. After drying and evaporation of the solvent, the product is purified by distillation under vacuum, which yields an (E+Z) isomer mixture in the form of an oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[S:11][C:12]([CH:15]=[N:16][OH:17])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Cl:20]N1C(=O)CCC1=O.O>CN(C)C=O>[OH:17][N:16]=[C:15]([Cl:20])[C:12]1[S:11][C:10]([O:9][C:8]2[CH:18]=[CH:19][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[N:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Oc1ccc(Oc2ncc(C=NO)s2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(Oc2ncc(C(Cl)=NO)s2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.5 %

Procedure:
To a solution of Example 1D (7.77 g, 0.028 mol) in N,N-dimethylformamide was added N-chlorosuccinimide (4.0 g, 0.029 mol) and the solution was stirred at room temperature for 6 hours. Water was added and the reaction mixture stirred for 30 minutes. The precipitate was filtered and air-dried to give 8.45 g of product as an off-white solid (96% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (d, J=5.88 Hz, 6H) 4.53-4.70 (m, 1 H) 6.95-7.07 (m, 2H) 7.26-7.37 (m, 2H) 7.67 (s, 1H) 12.41 (s, 1H). MS (ESI) m/z 294.0 (M−18)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([OH:14])[C:9]([OH:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[C:21]([NH:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([OH:14])[C:9]([OH:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1)(=[O:23])[CH3:22]
Reactant: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O

Procedure:
Approximately 1 mmol of 1-aminomethyl-3-phenyl-5,6-dihydroxy-3,4-dihydronaphthalene, from Example 2, was reacted with 1.2 mmol of acetic anhydride in the presence of 1.2 mmol of triethylamine in an excess of methylene chloride. The mixture was washed with 0.1N HCl, and dried. The product was precipitated by addition of ether, collected, and dried. mp 238° C. MS M/Z: 310. Anal. calc. for C19H19NO3.HBr C: 65.03; H, 5.72; N, 3.61; found: C, 73.46; H, 6.13; N, 4.49.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(OC(C)(C)C)=O)=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[N:15]2[CH2:21][C:20]([F:23])([F:22])[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:45]2[CH:46]=[C:41]([F:40])[CH:42]=[CH:43][C:44]=2[F:47])=[N:6][C:5]=1[C:7]([NH:9][C:10]1[CH:11]=[N:12][N:13]([CH3:31])[C:14]=1[N:15]1[CH2:21][C:20]([F:23])([F:22])[CH2:19][NH:18][CH2:17][CH2:16]1)=[O:8]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCN(C(=O)OC(C)(C)C)CC(F)(F)C1
Product: Cn1ncc(NC(=O)c2nc(-c3cc(F)ccc3F)sc2N)c1N1CCNCC(F)(F)C1
Yield: 28 %

Procedure:
Following the procedure for Example 105, reacting tert-butyl 4-(4-(2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate and 2,5-difluorophenylboronic acid gave 106 as a beige solid (57 mg, 28% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.88-7.81 (m, 2H), 7.18-7.10 (m, 1H), 7.06-6.99 (m, 1H), 6.16 (s, 2H), 3.78 (s, 3H), 3.70-3.56 (m, 2H), 3.44 (t, J=14.0 Hz, 2H), 3.35 (t, J=5.5 Hz, 2H), 3.11-3.05 (m, 2H), 1.95 (s, 1H). LCMS (ES+) m/z 470 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][C:17]([CH:21]=[CH2:22])=[C:16]2[CH2:23]O)=[O:9].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:3][CH2:23][C:16]1[C:15]2[C:20](=[C:11]([NH:10][C:8](=[O:9])[C:7]3[C:6]([Cl:5])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:29])[CH:12]=[CH:13][CH:14]=2)[N:19]=[CH:18][C:17]=1[CH:21]=[CH2:22]
Reactant: O=S(Cl)Cl
Reactant: C=Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CCl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
To N,N-dimethylformamide (1 ml) was added thionyl chloride (73.2 mg), and the mixture was stirred for 15 minutes at ambient temperature. To the mixture was added 8-(2,6-dichlorobenzoylamino)-4-hydroxymethyl-3-vinylquinoline (176.7 mg), and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added saturated sodium bicarbonate solution (10 ml) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature. The resulting precipitate was collected by filtration and washed with water to give 4-chloromethyl-8-(2,6-dichlorobenzoylamino)-3-vinylquinoline (182.8 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5].[N-:18]=[C:19]=[O:20].[K+]>C(O)(=O)C>[C:19]([NH:2][CH2:3][C:4]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5])(=[O:20])[NH2:18]
Reactant: CCOC(=O)C(NC(=O)CN)C(=O)OCC
Reactant: [N-]=C=O
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)C(NC(=O)CNC(N)=O)C(=O)OCC
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
To an aqueous solution of diethyl 2-(glycylamino)malonate hydrochloride (2.7 g) is added potassium isocyanate (1.6 g), and the mixture is stirred for 10 minutes. To the reaction mixture is added acetic acid (0.7 ml), and the mixture is further stirred for 5 hours. The reaction mixture is extracted with chloroform, and the extract is concentrated under reduced pressure. The residue is recrystallized from ethyl acetate to give diethyl 2-(N-carbamoylglycyl)aminomalonate (1.58 g), m.p. 140°-141.5° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]1([C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[C:4]1([C:10](=[N:2][OH:3])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NO
Reactant: COc1cccc(CC(=O)c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(CC(=NO)c2ccccc2)c1
Yield: 77.1 %

Procedure:
A solution of hydroxylamine hydrochloride (185.5 g, 2.67 mol) water (0.3 L) was added with stirring to a solution of 1-phenyl-2-(3-methoxyphenyl)ethanone (187 g, 0.89 mol) in 95% ethanol (1.4 L). Then, 0.3 L of 20% NaOH was added, with stirring, to the resulting mixture. The mixture was heated to reflux for 2 hrs, cooled, and the alcohol was evaporated with a water aspirator. The aqueous residue was extracted with ether (3×500 ml). The combined ether extracts were dried over MgSO4 and evaporated to provide a solid residue which was then recrystallized from cyclohexane (1 L) to provide 165.5 g (82%) of 1-phenyl-2-(3-methoxyphenyl)ethanone oxime. An analytical sample, recrystallized from ethylacetate/cyclohexane, had mp. 72°-73° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:19]1[CH2:24][N:23]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:22](=[O:30])[CH2:21][CH2:20]1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:49]=[N+:50]=[N-:51])(=O)=O)(C)C.CC(O)=O>C1COCC1>[N:49]([CH:21]1[CH2:20][CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=2[F:11])[CH2:24][N:23]([CH2:25][C:26]([F:29])([F:27])[F:28])[C:22]1=[O:30])=[N+:50]=[N-:51]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: O=C1CCC(c2cccc(F)c2F)CN1CC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: [N-]=[N+]=NC1CC(c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 26.3 mL, 26.3 mmol) in THF (120 mL) at −78° C. was added a cold (−78° C.) solution of 5-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)piperidin-2-one (6.42 g, 21.9 mmol) in THF (100 mL) dropwise, keeping the internal temperature of the reaction mixture below −65° C. The resulting mixture was stirred at −78° C. for 30 min, then a cold (−78° C.) solution of 2,4,6-triisopropylbenzenesulfonyl azide (Harmon et al. (1973) J. Org. Chem. 38, 11-16) (8.81 g, 28.5 mmol) in THF (80 mL) was added dropwise, keeping the internal temperature of the reaction mixture below −65° C. The reaction mixture was stirred at −78° C. for 45 min, then AcOH (6.0 mL, 105 mmol) was added. The resulting mixture was allowed to warm slowly to ambient temperature and was partitioned between saturated aqueous sodium bicarbonate (1 L) and CH2Cl2 (1.5 L). The organic layer was washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 40:60, to give the title compound. MS: m/z=334.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][S:9]([CH2:12][CH2:13][S:14]([OH:17])(=[O:16])=[O:15])(=[O:11])=[O:10])[CH2:6][O:5][C:4](=[O:7])[NH:3]1.C(O[Cl:23])(C)(C)C>CO>[Cl:23][N:3]1[C:2]([CH2:8][S:9]([CH2:12][CH2:13][S:14]([OH:17])(=[O:16])=[O:15])(=[O:10])=[O:11])([CH3:1])[CH2:6][O:5][C:4]1=[O:7]
Reactant: CC1(CS(=O)(=O)CCS(=O)(=O)O)COC(=O)N1
Reactant: CC(C)(C)OCl
Solvent: CO
Product: CC1(CS(=O)(=O)CCS(=O)(=O)O)COC(=O)N1Cl
Reaction time: 1 h
Yield: 40.4 %

Procedure:
To a solution of 2-((4-methyl-2-oxooxazolidin-4-yl)methylsulfonyl)ethanesulfonic acid (950 mg, 3.31 mmol) in MeOH (5 ml) was added, dropwise, tert-butylhypochlorite (500 ul, 4.2 mmol). The solution was stirred for 1 h, concentrated in vacuo, and purified by preparatory HPLC (H2O/MeOH) to afford the title compound as a clear oil (430.0 mg, 1.336 mmol, 40%). 1H NMR (D2O, 400 MHz) δ 1.60 (s, 3H), 3.3-3.4 (m, 2H), 3.6-3.7 (m, 2H), 3.80 (d, J=14.8 Hz, 1H), 3.96 (d, J=14.8 Hz, 1H), 4.47 (d, J=9.4 Hz, 1H), 5.05 (d, J=9.4 Hz, 1H). ESI/APCI expected for C7H12ClNO7S2: 320.97. Found: 320 (M−H+).
Reaction SMILES: C[O:2][C:3](=[O:48])[C@@H:4]([NH:17][C:18](=[O:47])[CH2:19][NH:20][C:21]([C:23]1[CH:46]=[CH:45][C:26]2[N:27]([CH3:44])[C:28]([NH:30][C:31]3[S:32][C:33]4[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:34]=4[N:35]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[OH-].[Na+]>CO.C1COCC1>[C:13]([O:12][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]([NH:17][C:18](=[O:47])[CH2:19][NH:20][C:21]([C:23]1[CH:46]=[CH:45][C:26]2[N:27]([CH3:44])[C:28]([NH:30][C:31]3[S:32][C:33]4[CH:39]=[C:38]([C:40]([F:42])([F:41])[F:43])[CH:37]=[CH:36][C:34]=4[N:35]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[C:3]([OH:48])=[O:2])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)ccc21
Yield: 88.5 %

Procedure:
(S)-6-tert-Butoxycarbonylamino-2-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-hexanoic acid (260 mg) was prepared by following General Procedure E starting from (S)-6-tert-butoxycarbonylamino-2-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-hexanoic acid methyl ester (300 mg) and 2 N NaOH (2 mL) in MeOH:THF (1:1, 2 mL).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[CH2:17]([O:24]C(CO)CO)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH:16]1[CH2:1][O:3][CH:4]([CH2:5][O:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(COCc1ccccc1)OCC
Reactant: OCC(CO)OCc1ccccc1
Product: c1ccc(COCC2OCC(OCc3ccccc3)CO2)cc1

Procedure:
Using the procedure of Example 47, benzyloxyacetaldehyde diethyl acetal and 2-benzyloxy-1,3-propanediol were reacted to give 5-benzyloxy-2-benzyloxymethyl-1,3-dioxane, nD25 1.5438. The ir spectrum was consistent with the assigned structure. The nmr spectrum indicated 28% cis isomer and 72% trans isomer.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:16][CH:17]=2)=[N:9][CH:10]=1.[CH2:24]([O:26][C:27](=[O:40])[CH2:28][C:29]1[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:31][NH:32][CH:33]=1)[CH3:25].O>CN(C)C=O>[CH2:24]([O:26][C:27](=[O:40])[CH2:28][C:29]1[C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:31][N:32]([CH2:4][C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[N:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:16][CH:17]=3)=[CH:7][CH:6]=2)[CH:33]=1)[CH3:25]
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Reactant: CCOC(=O)Cc1c[nH]nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-(2-phenyl-4-thiazolylmethoxy)pyridine (554 mg) and ethyl(3-phenyl-1H-pyrazol-4-yl)acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl(3-phenyl-1-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]acetate (594 mg, yield: 66%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 75–76° C.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH3:8][Si:9]([CH3:24])([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]1[CH2:17][O:16]1>C(O)C>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[CH2:17][CH:15]([OH:16])[CH2:14][O:13][CH2:12][CH2:11][CH2:10][Si:9]([CH3:8])([CH3:24])[CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Reactant: CC(C)NC(C)C
Solvent: CCO
Product: CC(C)N(CC(O)COCCC[Si](C)(C)CC[Si](C)(C)C)C(C)C
Temperature: 60 °C

Procedure:
Diisopropylamine (3.68 g, 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 60° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 60° C. for an additional 8 hours. Ethanol and diisopropylamine were stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[C:9]([Br:15])[CH:10]=[C:11]([Br:14])[CH:12]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:3])C.[NH:16]1C2C3C(=CC=CC=3C1=O)C=CC=2.BrBr>C(O)(=O)C>[Br:15][C:9]1[C:8]2[C:13]3[C:12](=[C:11]([Br:14])[CH:10]=1)[NH:16][C:1](=[O:3])[C:4]=3[CH:5]=[CH:6][CH:7]=2
Reactant: O=C1Nc2cccc3cccc1c23
Reactant: CC(=O)c1cccc2c(Br)cc(Br)cc12
Agent: BrBr
Solvent: CC(=O)O
Product: O=C1Nc2c(Br)cc(Br)c3cccc1c23

Procedure:
The 1-acetyl-5,7-dibromonaphthalene used in the foregoing procedure was prepared by dibromination of benz[cd]-indol-2(1H)-one with bromine in glacial acetic acid to give 41 g of 6,8-dibromobenz[cd]indol-2(1H)-one, m.p. 259°-260° C. The latter (12.8 g) was heated under reflux for one hour in two liters of 5% potassium hydroxide, the reaction mixture was cooled, filtered and then treated with 2.8 g of a solution of sodium nitrite in 50 ml of water. The resulting solution, cooled to 0° C., was added dropwise to 800 ml of a 40% solution of sulfuric acid while maintaining the temperature at -5° C. The reaction mixture was stirred for one hour, then poured slowly into a solution of 140 g of sodium hypophosphite in 800 ml of water at 0° C. with stirring. The solid which separated was collected by filtration and dissolved in 3 liters of 2% sodium carbonate solution, and the resulting solution was filtered, acidified with concentrated hydrochloric acid and the mixture extracted with ethyl acetate. The combined organic extracts were dried and taken to dryness to give 8 g of 5,7-dibromo-1-naphthalenecarboxylic acid which was heated with thionyl chloride in the presence of a small amount of DMF. The resulting crude 5,7-dibromo-1-naphthalenecarboxylic acid chloride, together with 6.0 g of methoxymethylamine hydrochloride in 750 ml of MDC, was treated dropwise at 0° C. with 60 ml of triethylamine in 250 ml of MDC. The reaction mixture was filtered, the filtrate was taken to dryness, and the resulting residue (12.0 g) was dissolved in THF and treated at 0° C. with stirring with a solution of 29.5 ml of 3M methyl magnesium bromide. The reaction mixture was stirred for ten minutes, quenched with water, taken to dryness and the residue partitioned between ethyl acetate and water. The mixture was filtered, the organic extracts were separated, dried and taken to dryness to give 9.9 g of 1-acetyl-5,7-dibromonaphthalene.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[C:6]([NH:9][CH:10]([C:32]([NH:34][CH2:35][C:36](=O)[CH2:37][C:38]([CH3:42])([CH3:41])[CH2:39][CH3:40])=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:20][N:21]([CH3:23])[CH:22]=2)=[CH:14][CH:13]=1)(=[O:8])[CH3:7]>C1(C)C(C)=CC=CC=1>[C:27]([O:26][C:25](=[O:31])[NH:24][C:19]1[C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH:10]([NH:9][C:6](=[O:8])[CH3:7])[C:32]3[NH:34][CH:35]=[C:36]([CH2:37][C:38]([CH3:41])([CH3:42])[CH2:39][CH3:40])[N:5]=3)=[CH:13][CH:14]=2)=[CH:22][N:21]([CH3:23])[N:20]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: CCC(C)(C)CC(=O)CNC(=O)C(Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1)NC(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(-c3cn(C)nc3NC(=O)OC(C)(C)C)cc2)NC(C)=O)n1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
Ammonium acetate (1.17 g, 15.2 mmol) was added to an ambient temperature solution of tert-butyl [4-(4-{2-(acetylamino)-3-[(4,4-dimethyl-2-oxohexyl)amino]-3-oxopropyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate (160 mg, 0.30 mmol) in xylene (5 mL). After stirring at 150° C. for 1 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate and methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded the title compound. (M+H) found: 509.