Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH2:12][OH:13])([CH2:10][OH:11])[CH2:8][OH:9])[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>C1COCC1>[OH:11][CH2:10][C:7]([C:5]1[O:4][N:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=1)([CH2:12][OH:13])[CH2:8][OH:9]
Reactant: Nc1cc(C(CO)(CO)CO)on1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(CO)(CO)CO)on1)Oc1ccccc1

Procedure:
To a stirred mixture of 2-(3-aminoisoxazol-5-yl)-2-(hydroxymethyl)propane-1,3-diol (1 equivalent) and potassium carbonate (2-5 equivalents) in anhydrous THF at rt is added phenyl chloroformate (1-2 equivalents), then stirring is continued at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is concentrated under reduced pressure and the residue is partitioned between water and dichloromethane. The organic layer is separated and the aqueous layer is further extracted with dichloromethane. The combined extracts are washed with water or brine, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford phenyl 5-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)isoxazol-3-ylcarbamate.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[N:19]2[CH:20]=[CH:21][N:22]=[C:23]([N:24]3[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]3)[C:18]2=[CH:17][CH:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([NH:29][C@H:26]3[CH2:27][CH2:28][N:24]([C:23]4[C:18]5[N:19]([N:15]=[CH:16][CH:17]=5)[CH:20]=[CH:21][N:22]=4)[CH2:25]3)=[O:14])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N[C@H]1CCN(c2nccn3nccc23)C1
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(c2nccn3nccc23)C1)c1ncn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of 1-phenyl-1H-1,2,4-triazole-3-carboxylic acid (0.093 g, 0.49 mmol, 1.4 eq) and (S)-1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-amine (0.10 g, 0.36 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.20 mL, 1.4 mmol, 2.6 eq) and HATU (0.21 g, 0.55 mmol, 1.5 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by HPLC to afford (S)-1-phenyl-N-(1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)-1H-1,2,4-triazole-3-carboxamide (0.095 g, 0.25 mmol, 52%). 1H NMR (400 MHz, CD3OD) δ 9.13 (s, 1 H), 8.16 (d, J=2.4 Hz, 1 H), 8.09 (d, J=5.8 Hz, 1 H), 7.86 (d, J=7.8 Hz, 2 H), 7.60-7.46 (m, 4 H), 7.19 (d, J=5.5 Hz, 1 H), 4.95-4.80 (m, 1 H), 4.78-3.80 (br, 4 H), 2.62-2.40 (m, 2 H); MS: (ES) m/z calculated for C19H18N8O [M+H]+ 375.2, found 375.
Reaction SMILES: [C:1]1([C:7]2(O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:13]=[N+:14]=[N-:15].[Na+].[C:17](O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[C:7]1([C:1]2([N:13]=[N+:14]=[N-:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: OC1(c2ccccc2)CCCC1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NC1(c2ccccc2)CCCCC1
Yield: 92.4 %

Procedure:
1-Phenylcyclopentanol (16.3 g, 100 mmol) was treated with NaN3 (s) (20 g, 310 mmol) and TFA (65 g) in CHCl3 (170 mL) at about 0-5° C., according to the procedure described in Preparation 87, to produce crude 1-phenyl-cyclohexylazide (18.6 g, GC-MS m/z 187).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1(=O)O[C:29](=[O:30])[CH:28]=C1.C=CCCCCCCCC.[C:43]1(=[O:49])[O:48][C:46](=[O:47])[CH:45]=[CH:44]1.C=CCCCCCCCCCCCC.[CH:64]([O:66][CH:67]=C)=[CH2:65]>>[C:4]1(=[O:5])[O:6][C:1](=[O:7])[CH:2]=[CH:3]1.[CH2:8]([O:30][CH:29]=[CH2:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[C:46]1(=[O:47])[O:48][C:43](=[O:49])[CH:44]=[CH:45]1.[CH3:67][O:66][CH:64]=[CH2:65]
Reactant: C=COC=C
Reactant: C=CCCCCCCCCCCCCCCCC
Agent: C=CCCCCCCCC
Agent: C=CCCCCCCCCCCCC
Agent: O=C1C=CC(=O)O1
Product: C=COC
Product: C=COCCCCCCCCCCCCCCCCCC

Procedure:
The cyclic carboxylic anhydride can be used in an amount of about 10-70, preferably about 35-70 mol percent. More preferably 45-60 mol percent of ethylenically unsaturated cyclic anhydride is copolymerized with 40-55 mol percent of at least one C2 to C30 aliphatic 1-alkene to produce a copolymer such as, e.g., a maleic anhydride/octadecene copolymer, maleic anhydride/decene copolymer, and maleic anhydride/tetradecene copolymer. It is also contemplated to copolymerize 45-60 mol percent of a cyclic carboxylic anhydride with 40-50 mol percent of a vinylether of preferably less than 30 carbon atoms to produce a copolymer such as, e.g. a maleic anhydride/octadecyl vinylether copolymer or maleic anhydride/methylvinylether copolymer. It is further contemplated to copolymerize 45-60 mole percent of a cyclic carboxylic anhydride with 40-55 mol percent styrene to produce, e.g. a maleic anhydride/styrene copolymer.
Reaction SMILES: CS(OC[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])=[C:21]([CH2:32][O:33][CH3:34])[CH:20]=3)[O:16][N:15]=2)[CH:9]=1)(=O)=O.[C:35](=O)([O-])[O-].[K+].[K+].Cl.[CH3:42][NH:43][CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>O1CCOCC1.C(Cl)Cl.O>[CH3:34][O:33][CH2:32][C:21]1[CH:20]=[C:19]([C:17]2[O:16][N:15]=[C:14]([C:10]3[CH:9]=[C:8]([CH2:7][CH2:42][N:43]([CH3:35])[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH:13]=[CH:12][CH:11]=3)[N:18]=2)[CH:24]=[CH:23][C:22]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Reactant: COCc1cc(-c2nc(-c3cccc(CCOS(C)(=O)=O)c3)no2)ccc1-c1ccccc1C
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COCc1cc(-c2nc(-c3cccc(CCN(C)CC(=O)OC(C)(C)C)c3)no2)ccc1-c1ccccc1C
Temperature: 130 °C
Yield: 81.5 %

Procedure:
To a solution of 2-(3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenethyl methanesulfonate (0.2 mmol) in dioxane (2 mL) was added potassium carbonate (165 mg, 1.2 mmol) and tert-butyl N-methylglycinate, hydrochloride salt (0.60 mmol). The mixture was heated at 130° C. for 72 hours, diluted with DCM (5 mL) and water (5 mL). The aqueous layer was extracted with DCM (3×20 mL), the combined organic fractions were dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, Pet Ether/EtOAc) to give the title compound as a colorless oil (86 mg, 72%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][S:12][C:13]1[S:14][C:15]2[CH:21](O)[CH2:20][CH2:19][CH2:18][C:16]=2[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:30]([O:38][CH2:39][CH3:40])(=[O:37])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].[H-].[Na+].Cl>O1CCCC1.C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][S:12][C:13]1[S:14][C:15]2[CH:21]([CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30]([O:38][CH2:39][CH3:40])=[O:37])[CH2:20][CH2:19][CH2:18][C:16]=2[N:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCCc2nc(SCc3cccc(Oc4ccccc4)c3)sc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C1CCCc2nc(SCc3cccc(Oc4ccccc4)c3)sc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A mixture of 2-[(3-phenoxybenzyl)thio]-4,5,6,7-tetrahydro-1,3-benzothiazol-7-ol (2.00 g, 5.41 mmol), thionyl chloride (0.723 mL) and toluene (10 mL) was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was dissolved in tetrahydrofuran (10 mL). The solution was added to a mixture of diethyl malonate (1.60 g, 10 mmol), sodium hydride (60% in oil, 400 mg) and tetrahydrofuran (20 mL) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was neutralized with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (AcOEt:hexane=1:19-2:1) to give the title compound (2.73 g, quantitative) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[CH:4]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:6]1[C:7]([OH:9])=[N:8][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:4][C:5]=1[OH:10])([O-:15])=[O:14]
Reactant: Oc1cc(O)nc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(O)cc(C(F)(F)F)nc1O
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
6-Trifluoromethyl-pyridine-2,4-diol (56 gm, 310 mmol) was added in 3-5 gm portions to conc. sulphuric acid (140 mL) with stirring to give a pale brown solution. The temperature increased to ˜50° C. during the addition. Nitric acid (21.1 mL 328 mmol, 70% HNO3 d=1.4 gm/ml) was added drop wise at such a rate as to maintain a reaction temperature of between 45° and 50° C. which took approximately 90 minutes. Once all the nitric acid had been added the reaction was allowed to cool to ambient temperature over 3 hours. The reaction mixture was then poured into ice/water (˜1.3 kg) with stirring, and after a few minutes a pale yellow precipitate formed which was filtered off, dissolved in ethyl acetate and dried over sodium sulphate, filtered and evaporated. A second crop of material was obtained by extraction of the aqueous filtrate with ethyl acetate. Combined batches and purified by crystallization from ethyl acetate/ n-heptane gave the title compound as a white ‘fluffy’ solid (49.5 gm 71% yield).
Reaction SMILES: [OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](=[O:6])[CH2:4][OH:5].[C:26](OCC(F)(F)F)(=[O:30])[CH2:27][CH2:28][CH3:29]>C(C(C)=O)C>[OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](=[O:6])[CH2:4][O:5][C:26](=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC(=O)OCC(F)(F)F
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Solvent: CCC(C)=O
Product: CCCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
A mixture of 1 g of 17α,21-dihydroxy-pregna-4-ene-3,20-dione and 10 ml of trifluoroethyl butanoate in 50 ml of methyl ethyl ketone was reacted at 45° C. in the presence of 5 g of Candida cylindracea lipase for 8-10 hours, adding at regular time intervals 1 g of lipase. After completion of the reaction, the lipase was filtered off, the filtrate was concentrated under vacuum, taking up the residue three times with solvent. The semi-solid residue was purified by chromatography on a silica gel column with a dichloromethane/methanol 99:1 mixture. The richer fraction was evaporated to obtain 0.89 g (2.14 mM) of 17α-hydroxy-21-butanoyloxy-pregna-4-ene-3,20-dione.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[CH:34]=2)=[O:12])=[C:6]([O:41][CH3:42])[CH:5]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[CH:34]=4)[C@H:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][C:6]=4[O:41][CH3:42])=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2ccc(F)c(Cl)c2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′R,5′S)-6-chloro-4′-(3-chloro-4-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester (0.2 g, 0.32 mmol) in MeOH (3 mL) and THF (9 mL) was added an aqueous solution (1N) of NaOH (6 mL, 6 mmol). The reaction mixture was stirred at room temperature for 18 h. The crude mixture was diluted with water (5 mL), and acidified to “pH” 5-6 by dilute aqueous HCl solution. The mixture was then extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-4-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid as a off white powder (Yield, 0.16 g, 82%).
Reaction SMILES: CC[C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH3:20])[C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=O.[OH-].[K+]>C(O)C.O>[CH3:3][NH:5][C:6]1[S:7][CH:8]=[C:9]([CH3:20])[C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: CCC(=O)Nc1scc(C)c1C(=O)c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNc1scc(C)c1C(=O)c1ccccc1Cl
Temperature: 95 °C

Procedure:
To a solution of 29.6 g of 2-(N-methylacetylamino)-3-(o-chlorobenzoyl)-4-methylthiophene in 592 ml of ethanol, is added 6.97 g of potassium hydroxide in 190 ml of water. The mixture is heated at 95°C for 1 hour, evaporated under reduced pressure to a residue. Water is added to the residue and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, then evaporated under reduced pressure to give an oil. The residual oil is chromatographed on silica gel, using chloroform as an eluent to give 2-methylamino-3-(o-chlorobenzoyl)-4-methylthiophene as crystals having a melting point of 132° - 134°C (after recrystallization from ethanol).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][N:22]=2)[CH:15]=[CH:14][C:13]=1[C:23]1[C:24]([S:29]([N:32]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[C:40]=2[CH3:45])COCCOC)(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1.[Si](Cl)(C)(C)C.[Na+].[I-].O>CC#N.CCOC(C)=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][N:22]=2)[CH:15]=[CH:14][C:13]=1[C:23]1[C:24]([S:29]([NH:32][C:39]2[O:43][N:42]=[C:41]([CH3:44])[C:40]=2[CH3:45])(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CN1Cc2ccccc2C1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN2Cc3ccccc3C2=O)c1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of the title compound of Step (A) in 4 ml of CH3CN, Me3SiCl (174 mg, 1.6 mmol) was added and followed by NaI (240 mg, 1.6 mmol). The mixture was stirred at room temperature for 20 min. Additional Me3SiCl (74 mg, 1.6 mmol) and NaI (240 mg, 1.6 mmol) were added in four portions and the reaction was stirred for additional 1 hr and 10 min. The reaction mixture was then added to 3 ml H2O and 30 ml EtOAc. The organic layer was separated and washed with 1 ml saturated aqueous Na2S2O3, brine, dried and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 30% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 70% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (43 mg, 40% for two steps) as a white solid, m.p. 135°-142° C. (amorphous).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1.[CH3:19][NH:20][CH2:21][CH3:22]>CO>[Cl:1][C:2]1[N:11]=[C:10]([N:20]([CH2:21][CH3:22])[CH3:19])[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CCC2
Reactant: CCNC
Solvent: CO
Product: CCN(C)c1nc(Cl)nc2c1CCCC2c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of 2,4-dichloro-8-phenyl-5,6,7,8-tetrahydroquinazoline (53.9 mg, 0.193 mmol) in methanol (1 mL) was added N-methylethanamine (0.033 mL, 0.386 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 2-chloro-N-ethyl-N-methyl-8-phenyl-5,6,7,8-tetrahydroquinazolin-4-amine (42.9 mg, 0.141 mmol, 72.9% yield) as colorless oil. LC-MS (M+H)+=302.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.25 (2H, t, J=7.5 Hz), 7.13-7.20 (1H, m), 7.01 (2H, d, J=7.3 Hz), 4.06-4.14 (1H, m), 3.42-3.53 (2H, m), 3.05 (3H, s), 2.56-2.74 (2H, m), 2.17-2.27 (1H, m), 1.76-1.89 (2H, m), 1.52-1.64 (1H, m), 1.24 (3H, t, J=7.2 Hz).
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[CH2:5](O)[CH2:6][CH:7]([OH:9])[CH3:8]>>[CH:3]([CH:1]1[O:9][CH:7]([CH3:8])[CH2:6][CH2:5][O:2]1)=[CH2:4]
Reactant: C=CC=O
Reactant: CC(O)CCO
Product: C=CC1OCCC(C)O1

Procedure:
Acrolein and 1,3-butanediol were condensed to produce 2-vinyl-4-methyl-1,3-dioxane in accordance with the procedure of Example I.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[S:19]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:8]=[CH:9][C:2]=1[Cl:1])(=[O:21])(=[O:20])[CH3:18]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)c(COS(C)(=O)=O)c1
Temperature: 0 °C
Yield: 100 %

Procedure:
To an ice cooled solution of 2-chloro-5-(Boc-amino)benzyl alcohol (7.4 g; 29 mmol; from step (i) above) in CH2Cl2 (100 mii) was added TEA (2.9 g; 29 mmol), followed by MsCl (3.3 g, 29 mmol; added dropwise). After stirring for 2 hours the resultant mixture was poured onto water. The organic layer was separated, washed with water, dried (Na2SO2) and concentrated to yield 10 g (100%) of the sub-title compound.
Reaction SMILES: ClC1C=C(C)C=C(C)C=1N1CCCC2=C(N)N(C)N=C12.C[N:22]1[C:30]([NH2:31])=[C:29]2[C:24]([N:25]([C:32]3[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=3[CH3:40])[CH2:26][CH2:27][CH2:28]2)=[N:23]1.C(Cl)(=O)CC.[CH3:46][O:47][CH2:48][C:49](Cl)=O>>[CH3:46][O:47][CH2:48][CH2:49][NH:31][C:30]1[NH:22][N:23]=[C:24]2[C:29]=1[CH2:28][CH2:27][CH2:26][N:25]2[C:32]1[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=1[CH3:40]
Reactant: COCC(=O)Cl
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(C)c1
Agent: CCC(=O)Cl
Agent: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(Cl)c1
Product: COCCNc1[nH]nc2c1CCCN2c1c(C)cc(C)cc1C

Procedure:
Compound 5-54 was prepared according to the procedure described in Example 15, steps 1 and 2, except that in step 1, 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (5-45) was replaced with 2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (5-52) and propionyl chloride was replaced with methoxyacetyl chloride.
Reaction SMILES: [CH3:1][O:2][P:3]([C@@H:6]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH3:7])(=O)[OH:4].C(Cl)(=O)C(C)(C)C.[OH:26][C@@H:27]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:28]([O:30][CH3:31])=[O:29].NCCCCC(O)C(O)=O>O1CCCC1.C(N(CC)CC)C>[CH2:12]([O:11][C:9]([NH:8][C@H:6]([P:3]([O:2][CH3:1])([O:26][C@@H:27]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:28]([O:30][CH3:31])=[O:29])=[O:4])[CH3:7])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COP(=O)(O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](O)CCCCNC(=O)OC(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Agent: NCCCCC(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)OP(=O)(OC)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
(R)-1-(benzyloxycarbonylamino)ethylphophonic acid monomethyl ester (40.7 mg) described in Biochemistry, 6294(1989) was dissolved in tetrahydrofuran (1 ml), and pivaloyl chloride (71.8 mg) and triethylamine (90.4 mg) were added. The mixture was stirred at room temperature for 30 minutes, then added with a tetrahydrofuran (1 ml) solution of methyl (S)-2-hydroxy-6-(tert-butoxycarbonylamino)hexanoate (38.9 mg), which is obtainable from 6-amino-2-hydroxyhexanoic acid described in Chem. Pharm. Bull., 621(1976) by a conventional method, and stirred at room temperature overnight. The organic substances were extracted with ethyl acetate and the extract was washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel thin-layer chromatography to obtain methyl (S)-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(methoxyphosphinoyl)oxy)-6-(tert-butoxycarbonylamino)hexanoate (9.7 mg, 13%). This compound was subjected to the measurement of molecular weight and then used in the following reaction.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH:24]=[O:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100.5 %

Procedure:
A solution of oxalyl chloride (6 mL, 70 mmol) in dichloromethane (60 mL) at −78° C. was treated dropwise with dimethyl sulfoxide (10 mL, 0.14 mol). After 15 minutes, 1-tert-butoxycarbonyl-4-piperidinemethanol (3.0 g, 14 mmol) was added as a solution in dichloromethane (35 mL). The mixture was stirred at −78° C. for 1 hr, then triethylamine (29 mL, 0.21 mol) was added dropwise. The mixture was warmed to ambient temperature and poured into a saturated ammonium chloride solution (200 mL). The organic layer was separated and the aqueous layer was washed with dichloromethane (75 mL). The organic layers were combined and washed with brine (75 mL); then dried with MgSO4, filtered and concentrated. The residue was redissolved in ethyl acetate-hexanes (1:1) and filtered through Florisil (100-200 mesh). The resulting filtrate was concentrated yielding 3.0 g (100%) of the title aldehyde as a yellow oil; which was used without further purification.