Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[N:6][CH:7]=1.[C:25]([O:29][C:30]([N:32]1[CH2:40][CH2:39][CH:35]([C:36](O)=[O:37])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.CN(C)CCCN=C=NCC>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:40][CH2:39][CH:35]([C:36](=[O:37])[NH:1][C:2]2[CH:7]=[N:6][C:5]([O:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[O:15][CH:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][CH2:12]4)=[CH:4][CH:3]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(Oc3ccc4c(c3)CCC(c3ccccc3)O4)nc2)CC1

Procedure:
5-Amino-2-(2-phenylchroman-6-yloxy)-pyridine (500 mg) and N-(tert-butoxycarbonyl)isonipecotic acid (541 mg) was dissolved in 40 ml of THF. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (451 mg) was added. The mixture was refluxed for few hours. Reaction was quenched with addition of water and extracted with ethyl acetate. Combined organic layers were washed with water, saturated sodium carbonate solution, dried with Na2SO4 and evaporated. 1H-NMR (300 MHz; d6-DMSO) δ: 10.0 (s, 1H), 8.31 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.33 (m, 5H), 6.92 (d, 1H, J 8.8 Hz), 6.87-6.84 (m, 3H), 5.13 (dd, 1H, J 2.2, 10.1 Hz), 4.04-3.96 (m, 2H), 2.99-2.91 (m, 1H), 2.81-2.69 (m, 3H), 2.20-2.12 (m, 2H), 2.08-1.98 (m, 1H), 1.79-1.74 (m, 3H), 1.50-1.35 (m, 11H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28](C)([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=2)[CH:7]=1.CS(C1C=CC(N2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC2=O)=CC=1)(=O)=O.ClC(OC(C)C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([O:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)cc2Cl)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: CC(OC(=O)Cl)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)cc2Cl)CC1

Procedure:
Example 268 was prepared according to procedures described in Example 2 substituting tert-butyl 4-(5-chloro-1-(4-cyano-3-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate in Step A and substituting isopropyl chloroformate for 1,1,1-trifluoropropan-2-yl chloroformate in Step C except that the crude product was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2). 1H NMR (400 MHz, CDCl3) δ ppm 7.67-7.87 (m, 1 H), 7.30-7.49 (m, 3 H), 6.00 (s, 1 H), 4.86-5.11 (m, 1 H), 4.53-4.70 (m, 1 H), 3.44-3.76 (m, 4 H), 1.79-2.15 (m, 4 H), 1.26 (s, 6 H). MS (ESI) 434 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([CH2:12][CH2:13][CH3:14])[CH:9]=[C:10]([Cl:11])[C:5]=2[O:4][C:3]=1C(O)=O.C1(C)C=CC=CC=1.Cl>C(O)(=O)C>[CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([CH2:12][CH2:13][CH3:14])[CH:9]=[C:10]([Cl:11])[C:5]=2[O:4][CH:3]=1
Reactant: CCCc1cc(Cl)c2oc(C(=O)O)c(C)c2c1O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCc1cc(Cl)c2occ(C)c2c1O
Yield: 74.6 %

Procedure:
A mixture of 3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran carboxylic acid (0.93 gm; 3.7 mmoles), toluene (25 mL), 6N hydrochloric acid (20 mL), 10N HCl (100 mL) and acetic acid (30 ml) was refluxed for a period of 18 hours. The two phases were separated and the organic phase was dried (Na2SO4), and concentrated in vacuo to yield 3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.62 gm; 80%), identical to the product obtained from the cyclisation reaction described above in Step C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]2[S:8][C:9]3[N:10]=[C:11]([NH2:18])[N:12]=[C:13]([S:16][CH3:17])[C:14]=3[N:15]=2)=[CH:4][CH:3]=1.[OH-].[Na+].I[CH3:24].O>CS(C)=O>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([C:7]2[S:8][C:9]3[N:10]=[C:11]([NH2:18])[N:12]=[C:13]([S:16][CH3:17])[C:14]=3[N:15]=2)[CH3:24])=[CH:4][CH:3]=1
Reactant: CSc1nc(N)nc2sc(Cc3ccc(F)cc3)nc12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CSc1nc(N)nc2sc(C(C)c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
To a solution of 2-(4-fluorobenzyl)-7-(methylthio)thiazolo[5,4-d]pyrimidin-5-amine (0.4 g, 1.31 mmol) and 2N NaOH (0.65 ml, 1.31 mmol) in DMSO (7 ml) was added iodomethane (81 μl, 1.31 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water and extracted with ethyl acetate, brine and dried over Na2SO4. After removing the solvents under reduced pressure, the residue was purified by chromatography on silica gel (hexane/EtOAc 5:1) yielding the title compound as a white solid (0.29 g, 69%).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:17][CH2:16][CH2:15][C@H:9]2[C:10]([O:12]CC)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[ClH:20]>C1COCC1.CCO.O>[ClH:20].[C:1]1([CH2:7][N:8]2[CH2:17][CH2:16][CH2:15][C@H:9]2[C:10]([OH:12])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@@H]1CCCN1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1CCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Ethyl 1-(phenylmethyl)-L-prolinate (13.20 g, 56.57 mmol) was dissolved in a mixture of THF (40 mL), EtOH (40 mL) and H2O (16 mL). To this solution was added solid sodium hydroxide (6.789 g, 169.73 mmol), and the mixture was stirred at room temperature overnight. The solution was adjusted to pH 2 with 1N aq. HCl and then extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo, and the resulting crude product was 1-(phenylmethyl)-L-proline hydrochloride (0.8 g). The aqueous layers were concentrated in vacuo, the residue was suspended in MeOH, and the resulting solid precipitate was collected by filtration and combined with the product from the organic extracts to provide 1-(phenylmethyl)-L-proline hydrochloride (13.30 g, 97%). LCMS: (M+H)+: 206.1
Reaction SMILES: [OH-].[Na+].CS(C)=O.C[O:8][C:9](=[O:22])[CH:10]([S:19][CH2:20][CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[C:23]([O:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:33][CH:32]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>O.O1CCCC1>[C:23]([O:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][O:18][C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH:10]([S:19][CH2:20][CH3:21])[C:9]([OH:8])=[O:22])=[CH:13][CH:14]=2)=[CH:33][CH:32]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCSC(Cc1ccc(O)cc1)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CCSC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.8 %

Procedure:
Sodium hydroxide (0.14 g; 3.5 mmole) was pulverized and added to DMSO (15 ml). 2-ethylsulfanyl-3-(4-hydroxyphenyl)propanoic acid methyl ester (described in Example 43b) (0.21 g, 0.87 mmole) was added and the resulting mixture was stirred at room temperature for 10 minutes before addition of 2-(4-(tert-butoxycarbonylamino)phenyl]ethyl-4-methylbenzenesulfonate (described in Example 40a) (0.342 g; 0.87 mmole). The reaction mixture was stirred at room temperature for 4 hours. Sodium hydroxide (1.08 g; 2.7 mmole) was dissolved in water (15 ml) and added to the reaction mixture followed by addition of tetrahydrofuran (5 ml). The reaction mixture was stirred at room temperature over night. Most of the solvents were evaporated. The residue was treated with diethyl ether and water and the phases were separated. The organic phase was dried with sodium sulfate and evaporated. Chromatography of the residue on silica gel using a gradient system of petroleum ether: diethyl ether (90:10, 75:25, 25;75 and 0:100) gave 0.41 g (34% yield) of 3-[4-{2-(4-[tert-butoxycarbonylamino]phenyl)ethoxy}phenyl]-2-ethylsulfanylpropanoic acid.
Reaction SMILES: [O:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].C(N(CC)CC)C.[C:15]1([C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:15]1([C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:3]2[C:4](=[O:6])[CH2:5][O:1][C:2]2=[O:7])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1COC(=O)N1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1COC(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of 600 mg of 2,4-oxazolidinedione and 601 mg of triethylamine in 7.0 ml of chloroform was added 1.66 g of triphenyl chloromethane and the reaction mixture stirred at room temperature for 30 minutes. The resulting mixture was dissolved in 250 ml of ethyl acetate and washed with water (3×50 ml) and brine (2×20 ml) and dried over sodium sulfate. Removal of the solvent gave 1.8 g of the desired product.
Reaction SMILES: [Br:1]Br.[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[OH:13]>CC(O)=O>[Br:1][C:10]1[CH:11]=[C:12]2[C:7]([N:6]=[CH:5][C:4]([OH:13])=[N:3]2)=[CH:8][CH:9]=1
Reactant: Oc1cnc2ccccc2n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Oc1cnc2ccc(Br)cc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
Bromine (0.895 mL, 15.5 mmol) was added to the solution of quinoxalin-2-ol (1.5 g, 10.3 mmol) in HOAc (15 mL), the mixture was stirred at r.t. for 6 h, and the precipitate was collected and washed with ethyl ether and dried to afford 7-bromoquinoxalin-2-ol as a solid in 90% yield (2 g).
Reaction SMILES: C([O:4][CH2:5][C:6]1([CH2:30][Cl:31])[C:11]2=[N:12][C:13]([C:25]([O:27]CC)=O)=[C:14]([O:17]CC3C=CC=CC=3)[C:15](=[O:16])[N:10]2[CH2:9][CH2:8][O:7]1)(=O)C.Cl.[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[C:36]([N:42]2[CH:46]=[N:45][C:44]([CH3:47])=[N:43]2)[CH:35]=1.C(N(CC)CC)C.C([O-])([O-])=O.[Cs+].[Cs+]>FC(F)(F)C(O)=O.C(O)C.O>[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:25]([C:13]2[N:12]=[C:11]3[N:10]([C:15](=[O:16])[C:14]=2[OH:17])[CH2:9][CH2:8][O:7][C:6]3([CH2:30][Cl:31])[CH2:5][OH:4])=[O:27])=[C:36]([N:42]2[CH:46]=[N:45][C:44]([CH3:47])=[N:43]2)[CH:35]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(CCl)COC(C)=O
Reactant: Cc1ncn(-c2cc(F)ccc2CN)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ncn(-c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2O)CCOC3(CO)CCl)n1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
A solution of ethyl 9-(acetoxymethyl)-3-(benzyloxy)-9-(chloromethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate (1.0 g) in trifluoroacetic acid (5 mL) CH2Cl2 (5 mL) was stirred for 2 hrs. An aliquot was transferred to a separate reaction flask and concentrated to give des-OBn intermediate (0.363 g, 1.01 mmol). This was immediately dissolved in dimethylfomamide (2 mL) and ethanol (2 mL) and treated with (4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzylamine hydrochloride (0.320 g, 1.31 mmol) and triethyl amine (0.75 mL, 5.2 mmol), and heated (90° C.) for 5 hrs. To the reaction was added Cs2CO3 (0.340 g, 1.1 mmol) and water (1 mL) and the reaction stirred for 2.5 hrs. The reaction was concentrated in-vacuo and the resultant crude material was suspended in water (10 mL) and extracted into CH2Cl2 (2×10 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to give a solid which was then triturated with a small volume of 95% ethanol. The resultant precipitate was collected by filtration and dried in-vacuo to give the title compound as a white crystalline solid: 1H NMR (500 MHz, CDCl3) δ ppm 12.18-12.31 (1H, m), 8.49 (1H, t, J=6.26 Hz), 8.32 (1H, s), 7.67 (1H, dd, J=8.39, 5.95 Hz), 7.19 (1H, dt, J=8.16, 2.29 Hz), 7.08 (1H, dd, J=8.39, 2.29Hz), 5.29 (2H, s), 4.54 (1H, dd, J=14.19, 6.87 Hz), 4.19-4.27 (1H, m), 4.12-4.18 (1H, m), 4.10 (2H, t, J=4.58 Hz), 4.00 (2H, t, J=12.21 Hz), 3.90-3.96 (2H, m), 2.55 (3H, s); 13C NMR (126 MHz, CDCl3) δ ppm 167.69, 163.26, 162.49, 157.34, 147.41, 146.32, 144.26, 134.31, 134.24, 128.45, 128.42, 125.59, 116.93, 116.76, 112.41, 112.21, 80.41, 66.93, 60.79, 53.52, 48.62, 42.47, 39.41, 14.12; HRMS ESI) calcd for C20H21N6O5FCl (M+H) 479.1246, found 479.1224; Elem. Anal. calcd for C20H20N6O5FCl: C 49.79, H 4.26, N 17.42, found: C 50.11, H 4.10, N 17.28.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([CH:23]=2)[CH2:21][CH2:20][S:19]3)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([CH:23]=2)[CH2:21][CH2:20][S:19]3=[O:32])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1cc(-c2cn3c(n2)SCC3)cc(C(C)(C)C)c1O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(-c2cn3c(n2)S(=O)CC3)cc(C(C)(C)C)c1O
Yield: 77.5 %

Procedure:
In 10 ml of chloroform was dissolved 1.6 g of 6-(3,5-di-tertbutyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole and after adding thereto 1 g of m-chloroperbenzoic acid, the mixture was stirred for 10 minutes. The reaction mixture was washed with an aqueous 5% sodium hydrogen carbonate solution, dried, and then the solvent was distilled off. The crystals thus formed were recrystallized from ethanol to provide 1.3 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole 1-oxide as the 1/2 ethanol addition product.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[O:12])=[C:6]([O:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:5]=1.[OH-].[Li+].Cl>CO>[CH3:20][C:17]1[N:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[CH:5][C:6]=2[O:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:15][CH:16]=1
Reactant: COC(=O)c1ccc(NC(=O)Nc2cnc(C)cn2)c(OCc2cccnc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cnc(NC(=O)Nc2ccc(C(=O)O)cc2OCc2cccnc2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a stirred solution of 4-[3-(5-methyl-pyrazin-2-yl)-ureido]-3-(pyridin-3-ylmethoxy)-benzoic acid methyl ester (1.3 gm; 3.3 mmol) in methanol (25 mL) was added lithium hydroxide (5 mL of a 2M aqueous solution). The reaction was heated to 60 degrees and stirred for 12 hours. The reaction was allowed to cool to room temperature and the pH was adjusted to 5.5 with 1N hydrochloric acid. A precipitate formed which was filtered and dried under reduced pressure to yield the desired product as a tan solid (90% yield). 1H-NMR (400 MHz, d6-DMSO) δ 10.29 (s, 1H), 8.79 (s, 1H), 8.68 (d, 1H), 8.59 (br s, 1H), 8.48 (d, 1H), 7.70 (s, 1H), 7.62 (d, 1H), 7.51 (m, 1H), 5.32 (s, 2H), 2.32 (s, 3H).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Si:13]([O:30][CH2:31][C@@H:32]([NH2:46])[CH2:33][NH:34][CH2:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Si:13]([O:30][CH2:31][C@@H:32]1[CH2:33][N:34]([CH2:35][C:36]23[CH2:37][CH:38]4[CH2:39][CH:40]([CH2:41][CH:42]([CH2:44]4)[CH2:43]2)[CH2:45]3)[C:5](=[O:11])[NH:46]1)([C:26]([CH3:27])([CH3:28])[CH3:29])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](OC[C@@H](N)CNCC12CC3CC(CC(C3)C1)C2)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OC[C@@H]1CN(CC23CC4CC(CC(C4)C2)C3)C(=O)N1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 156.3 %

Procedure:
A solution of triphosgene (124 mg, 0.42 mmol) in anhydrous CH2Cl2 (2 mL) was added slowly to a solution of (S)-3-(tert-butyldiphenylsilyloxy)-N1-(1-adamantylmethyl)propane-1,2-diamine (600 mg, 1.26 mmol) and triethylamine (140 mg, 1.4 mmol) in anhydrous CH2Cl2 (10 mL) at 0° C. The reaction mixture was stirred for another 1 h. The mixture was diluted with water and extracted with CH2Cl2 (50 mL). The organic layer was washed with 0.1 N aq HCl (2×20 mL) and brine (10 mL), dried over MgSO4 and concentrated to give a residue, which was purified by preparative TLC to provide (S)-4-((tert-butyldiphenylsilyloxy)methyl)-1-(1-adamantylmethyl)imidazolidin-2-one (330 mg, 52%). 1H NMR: (CDCl3, 400 MHz): δ=1.05 (s, 9H), 1.54 (s, 6H), 1.62-1.73 (m, 8H), 1.98 (s, 3H), 2.77 (m, 2H), 3.21 (m, 1H), 3.55 (t, 1H), 3.65 (m, 2H), 3.82 (m, 1H), 4.57 (s, 1H), 7.4 (m, 6H), 7.62 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:23]([NH:25][NH:26][CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30])=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]1([CH2:41][C:42](O)=[O:43])[CH:40]=[CH:39][N:38]=[CH:37]1>>[CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:23]([NH:25][N:26]([C:42](=[O:43])[CH2:41][N:36]1[CH:40]=[CH:39][N:38]=[CH:37]1)[CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30])=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Reactant: O=C(O)Cn1ccnc1
Product: CC[C@H](C)CN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1)C(=O)Cn1ccnc1

Procedure:
In a manner analogous to that described in Example 8 from (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-4-methyl-2′-(2(S)-methylbutyl)valerohydrazide and using imidazole-1-acetic acid in place of N-tert-butoxycarbonyl-β-alanine in Example 8 there was obtained (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-[2-(1H-imidazol-1-yl)acetyl]-4-methyl-2′-(2(S)-methylbutyl)valerohydrazide in the form of a gum.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)(=[O:14])=[O:13])[C:9](=[O:24])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[C:1]1([CH:7]2[CH2:11][N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:19][CH2:18]4)(=[O:14])=[O:13])[C:9](=[O:24])[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1NC(c2ccccc2)CN1S(=O)(=O)c1ccc2c(c1)CCN2
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)N1CCc2cc(S(=O)(=O)N3CC(c4ccccc4)NC3=O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4-Phenyl-1-(indoline-5-sulfonyl)-4,5-dihydro-2-imidazolone (0.20 g, 0.58 mmol) prepared in Preparation 5 was dissolved in 12 m of dichloromethane. Pyridine (0.1 m, 0.58 mmol) and benzoyl chloride (0.1 g, 0.58 mmol) were added dropwise one after another at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 2 hours and further stirred at room temperature for 3 hours. The reaction mixture was diluted with 20 m of dichloromethane, washed twice with 10 m of water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=2/1, v/v) to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH:7]=1>[OH-].[Na+].[Zn]>[N:14]1[N:13]([C:8]2[CH:7]=[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[CH:11]=[CH:10][C:9]=2[OH:12])[N:21]=[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=12
Reactant: O=[N+]([O-])c1ccccc1N=Nc1cc(CCCCO)ccc1O
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Product: OCCCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 86.5 %

Procedure:
6.03 g (18 mmols) of crude 4-(4-hydroxybutyl)-2-[(2-nitrophenyl)azo]phenol synthesized in Example 15 was dissolved in 18 ml of aqueous solution of 2N sodium hydroxide. 9 ml of previously prepared aqueous solution of 25% sodium hydroxide and 5.4 g (83 mmols) of zinc powder were simultaneously added over a period of about 3 hours. The subsequent treatment was carried out in the same manner as in Example 6, giving 4.41 g of 2-(2H-benzotriazole-2-yl)-4-(4-hydroxybutyl)phenol as pale yellow crystals (yield 78%, purity 90%).
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](Br)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25](B2OC(C)(C)C(C)(C)O2)=[C:24]([CH3:35])[O:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH:17]=[C:16]([C:25]2[C:21]([CH3:20])=[N:22][O:23][C:24]=2[CH3:35])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=c1c2ccccc2c(Br)cn1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1noc(C)c1-c1cn(Cc2ccccc2)c(=O)c2ccccc12
Temperature: 100 °C
Reaction time: 17 h
Yield: 41.5 %

Procedure:
A mixture of 2-benzyl-4-bromoisoquinolin-1(2H)-one (0.320 g, 1.02 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.341 g, 1.53 mmol) and Na2CO3 (0.324 g, 3.06 mmol) in toluene (20 mL), ethanol (10 mL) and water (3 mL) was degassed under nitrogen. Pd(PPh3)4 (0.118 g, 0.10 mmol) was then added and the reaction was stirred at 100° C. for 17 h under nitrogen. After that time, the mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 hexanes/ethyl acetate to 75:25 hexanes/ethyl acetate) to give 2-benzyl-4-(3,5-dimethylisoxazol-4-yl)isoquinolin-1(2H)-one (0.140 g, 42%) as an off white solid: mp 139-141° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=7.8 Hz, 1H), 7.60-7.68 (m, 1H), 7.51-7.60 (m, 1H), 7.29-7.39 (m, 5H), 7.19 (d, J=7.8 Hz, 1H), 6.97 (s, 1H), 5.18-5.33 (m, 2H), 2.23 (s, 3H), 2.06 (s, 3H); ESI MS m/z 331 [M+H]+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20](=[O:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])(=O)=O>C(O)(=O)C>[C:1]([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20](=[O:22])[CH2:21][Cl:26])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(=O)CCl
Yield: 93.1 %

Procedure:
A solution of ethyl 2-(2-benzoyloxyethoxyimino)-3-oxobutyrate (syn isomer, 28 g.), sulfuryl chloride (13.5 g.) and acetic acid (30 ml.) was stirred at 40° C. for 10 minutes and at room temperature for 5.5 hrs. The reaction mixture was treated in a conventional manner to give ethyl 2-(2-benzoyloxyethoxyimino)-4-chloro-3-oxobutyrate (syn isomer, 29 g.).