Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:15])([F:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13]>C(#N)C.O>[N+:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([F:15])([F:14])[F:5])[C:8]=1[OH:13])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccccc1C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Reaction time: 0.17 h
Yield: 33.8 %

Procedure:
Acetyl nitrate obtained mixing acetyl anhydride (3.30 g, 33 mmol) with fuming nitric acid (2.05 g, 33 mmol) at 0° C. was dropped into a solution of 2-trifluoromethylphenol (4.86 mg, 30 mmol) in acetonitrile (60 ml) at 0° C. followed by stirring for 10 minutes. The reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (60 g of silica gel; developing solvent, hexane:methylene chloride=5:1) to provide 2.1 g (yield 33%) of 2-nitro-6-trifluoromethylphenol as pale yellow crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C:5]1=[O:11].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([OH:1])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH:1][CH2:2][CH2:3][C@@H:4]1[O:8][C:7]([CH3:9])([CH3:10])[O:6][C:5]1=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC1(C)OC(=O)[C@H](CCO)O1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: -4 °C

Procedure:
Dried (S)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane-4-one (9.0 g, 59.2 mmol) was dissolved in 100 mL of anhydrous pyridine under argon and cooled to -4° C. To this solution maintained at approximately 0° C. was added dropwise 11.3 g (59.22 mmol) of p-toluenesulfonyl chloride dissolved in 100 mL of pyridine. Following addition, the mixture was placed in the refrigerator (0°-4° C.) overnight. Water (150 mL) was added, and the aqueous mixture extracted with 4×200 mL of ether. The ether layers were combined, washed with 3×150 mL of water, 3×150 mL of saturated copper sulfate solution (until no dark blue color remained), 2×100 mL of water, 3×150 mL of brine, dried (Na2SO4), filtered, and evaporated under reduced pressure. The crude rosylate was purified by column chromatography using ethyl acetate:hexanes (1:1) to provide the title compound, 16.7 g (95%) as white solid: mp 48°-49° C.; [α]D25 -3.7°(C=0.3, CH3OH); IR (Kbr, cm-1) 2989, 1785, 1390, 1357, 1278; 1H NMR (CDCl3) δ 7.80 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.3 Hz, 2H), 4.43 (dd, J=4.4, 8.1 Hz, 1H), 4.27-4.14 (m, 2H), 2.46 (s, 3H), 2.3-2.17 (m, 1H), 2.09-1.92 (m, 1H), 1.58 (s, 3H), 1.51 (s, 3H); HRMS calculated for C14H18O6S (M+), 314.0824, found 314.0817.
Reaction SMILES: O=[C:2]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[N:6]=[C:5]1[CH2:17][NH:18]C(OCC1C=CC=CC=1)=O>CC(O)=O.[Pd]>[CH2:29]([CH:2]1[CH2:3][N:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])[N:6]=[C:5]2[CH2:17][NH:18]1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCC(=O)Cn1cc(-c2ccccc2OC)nc1CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCC1Cn2cc(-c3ccccc3OC)nc2CN1
Reaction time: 6 h

Procedure:
The product from Step 15.a. (compound xxiv, where R3, R5 and R6 are H, R5 is 2-methoxyphenyl, and R7 is n-butyl) (650 mg, 1.49 mmol) was dissolved in HOAc (25 ml) containing 10% Pd on carbon (65 mg) and the mixture was hydrogenated under 30 psi H2 for about 6 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated under reduced pressure to yield a pale yellow oil which crystallizes on standing (430 mg, 101%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([CH:22]=1)[C:20]#[N:21].O>CN(C)C=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:19]([CH:22]=1)[C:20]#[N:21]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: OCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(Br)ccc1OCCCCc1ccccc1
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
4-Phenylbutanol (0.834 g) was dissolved in N,N-dimethylformamide (10 ml), and sodium hydride (60%, 0.638 g) was added. After stirring for 30 min, 5-bromo-2-fluorobenzonitrile (0.640 g) was added, and the mixture was further stirred at 40-50° C. for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (1.04 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[N:18]=[C:19]2[N:23]([C:24]=1[C:25](O)=[O:26])[CH:22]=[CH:21][S:20]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH:15][C:25]([C:24]1[N:23]2[C:19]([S:20][CH:21]=[CH:22]2)=[N:18][C:17]=1[CH3:16])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Reactant: Cc1nc2sccn2c1C(=O)O
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)OC(C)(C)C

Procedure:
prepared by reaction of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester with 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (A. Andreani et al. Eur. J. Med. Chem. 1982, 17, 271-274).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([N:7]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:8][CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].[Cl:20][C:21]1[CH:39]=[CH:38][C:24]2[O:25][C:26]3[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=3[CH2:28][N:29]([C:30]([NH:32][NH2:33])=[O:31])[C:23]=2[CH:22]=1>O>[CH3:19][C:2]([CH3:1])([O:4][C:5]([N:7]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:8][CH2:9][C:10]([NH:33][NH:32][C:30]([N:29]1[CH2:28][C:27]2[CH:34]=[CH:35][CH:36]=[CH:37][C:26]=2[O:25][C:24]2[CH:38]=[CH:39][C:21]([Cl:20])=[CH:22][C:23]1=2)=[O:31])=[O:12])=[O:6])[CH3:3]
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N(CCC(=O)O)Cc1cccs1
Solvent: O
Product: CC(C)(C)OC(=O)N(CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)Cc1cccs1

Procedure:
1.1 mmol of 3-[[(1,1-dimethylethoxy)carbonyl](2-thienylmethyl)amino]propanoic acid (16), prepared as described above in Example 16, was reacted with 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, in the same manner described in Example 9. The yield of product was 0.31 g (51%). Analysis calculated for C27H29N4O5SCl.0.25 H2O (M.W. 561.57): C, 57.29; H, 5.34; N, 9.90. Found: C, 57.42; H, 5.40; N, 9.96.
Reaction SMILES: O.O.[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.N1C2C(=CC=CC=2)C=C[CH:15]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C2C(=CC=CC=2)C=CC=1.S(OC)(OC)(=O)=O>C(Cl)Cl.C1CCCCC1>[C:3]1([CH3:13])[CH:4]=[CH:5][C:6]([S:9]([O:12][CH3:15])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: c1ccc2ncccc2c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1ccc2[nH+]cccc2c1
Solvent: C1CCCCC1
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COS(=O)(=O)c1ccc(C)cc1

Procedure:
To a suspension of p-toluenesulfonic acid dihydrate (10 g, 0.05 mol) in methylene chloride (50 mL), quinoline (8.3 g, 0.06 mol) was added dropwise, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated to dryness under the reduced pressure to obtain a crude product containing quinolinium p-toluenesulfonate salt. To a suspension of this crude product (5 g, 0.016 mol) in cyclohexane (50 mL), dimethyl sulfate (4.2 g, 0.033 mol) was added, and the mixture was reacted at 80° C. for 2 hours. The reaction liquid was condensed under the reduced pressure to obtain the desired product of methyl p-toluenesulfonate. Quantitative analysis by 1H-NMR showed a conversion rate of 93%.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][CH:48]1[CH2:52][CH2:51][CH2:50][NH:49]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:49]4[CH2:50][CH2:51][CH2:52][CH:48]4[CH3:47])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CCCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCC2C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with 2-methyl-pyrrolidine (Aldrich) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C41H52Cl2N5O3 [(M+H)+] 761.3707, observed 761.3707.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[C:17]2[C:16](=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]([CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>CCOC(C)=O>[CH3:26][CH:25]([O:27][C:28](=[O:30])[CH3:29])[C:14](=[N:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:7])[C:17]=1[C:16](=[O:15])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CC(=O)OC(C)c1nc2cccc(C)c2c(=Nc2ccccc2)o1
Solvent: CCOC(C)=O
Product: CC(=O)OC(C)C(=Nc1cccc(C)c1C(=O)Nc1ccccc1)N1CCCCC1
Reaction time: 19.5 h

Procedure:
Piperidine (1 mL) was added to compound 178 (0.161 g, mmol) and the reaction mixture was stirred for 19.5 h. The reaction mixture was then concentrated under reduced pressure to give a yellow gum. Trituration with 1:4 EtOAc:hexanes gave a small amount of compound 179 (0.041 g). Flash chromatography (1:4 EtOAc:hexanes) of the filtrate gave only a partially separable mixture of the expected products, the acetoxyquinazolinone compound 179 and the hydroxyquinazolinone (total mass 0.122 g). ESI-MS m/z=408 (MH+). The reaction described above and compound 179 are shown below.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[S:8][C:6]=2[N:7]=1.[OH-].[Na+].[CH3:38]I>CN(C=O)C.ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH3:38])[S:8][C:6]=2[N:7]=1
Reactant: CI
Reactant: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(Cc3ccc(Cl)cc3)sc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(c1ccc(Cl)cc1)c1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a suspension of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(4-chlorophenylmethyl)thiazolo[5,4-d]pyrimidine (53 mg, 0.1 mmol) in DMF (2 ml) was added 1N NaOH (150 μl, 0.15 mmol) and MeI (7 μl, 0.11 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/80), yielding the pure title compound (40 mg, 74%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>N1C=CC=CC=1>[S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:15])=[O:14]
Reactant: COCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COCCCOS(=O)(=O)c1ccc(C)cc1
Yield: 132 %

Procedure:
37.9 g of 3-methoxypropanol and 53.9 g of p-toluenesulfonyl chloride in 50.2 g of pyridine were stirred for 3 hours while the reaction temperature is kept at 0 to 10° C. The product was extracted with ethyl acetate, to give 91.2 g of 3-methoxypropyl tosylate (yield: 89%). 55 g of the obtained 3-methoxypropyl tosylate and 39.0 g of 2,3,3,5-tetramethyl-3H-indole were blended at 120° C. for 3 hours and was cooled to room temperature. 47.7 g of 2,5-bis[(phenylamino)methylene]cyclopentylidenediphenylaminium tetrafluoroborate, 23.0 g of acetic anhydride, 56.9 g of triethylamine, and 220 ml of 2-propanol were added thereto, and the mixture was further stirred at 80° C. for 3 hours. After reaction, the mixture was allowed to cool to room temperature, and 90 ml of water was added thereto. The crystal precipitated was collected by filteration, and was washed sufficiently with water, to give 60.1 g of a cyanine colorant (IR-2) (yield: 80%). 15.0 g of the colorant (IR-2) obtained was dissolved in 90 ml of acetonitrile. The mixture was added dropwise into an aqueous solution containing 6.6 g of KPF6 in 90 g of water at room temperature over 15 minutes, and the resulting mixture was stirred for 2 hours after the dropwise addition. Then, the crystal precipitated was collected by filteration and dried, to give 15.2 g of a cyanine colorant (IR-3) (yield: 95%). Then, 5.0 g of the cyanine colorant obtained (IR-3) was dissolved in 50 ml of chloroform, 3.0 g of manganese dioxide was added thereto, and the mixture was stirred at room temperature for 48 hours. After removal of manganese dioxide by filtration, the filtrate was distilled for removal of chloroform, and the crude crystal obtained was resuspended in 20 ml of ethyl acetate, to give 4.5 g of (A-4) (yield: 90%).
Reaction SMILES: [CH3:1]N(C)C=O.O=P(Cl)(Cl)Cl.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:14][CH:13]=1.N>C(O)(=O)C.O>[CH3:11][C:12]1[CH:17]=[C:16]2[C:15](=[CH:14][CH:13]=1)[NH:18][C:19](=[O:27])[C:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:1]2
Reactant: Cc1ccc(NC(=O)Cc2ccccc2)cc1
Reactant: CN(C)C=O
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2[nH]c(=O)c(-c3ccccc3)cc2c1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 9.7 %

Procedure:
0.41 ml (5.3 mmol, 1.5 eq) of N,N-dimethylformamide is added dropwise to 3.3 ml (25 mmol, 7 eq) of POCl3, under a nitrogen atmosphere and at −30° C. The medium is stirred for 15 min at −30° C. and 800 mg of amide 47 (3.5 mmol) are then added. The reaction mixture is warmed to room temperature with stirring and the reaction is then heated at 75° C. for 1.5 h. At the end of the reaction, this solution is poured onto crushed ice, neutralized with aqueous 30% ammonia solution and then extracted with dichloromethane. The organic phase is dried over MgSO4 and then evaporated. The residue obtained is dissolved in 5.4 ml of glacial acetic acid and 0.2 ml of water and the final solution is then refluxed for 3 h. The acetic acid is evaporated off. The residue is dissolved in water, neutralized with 25% sodium hydroxide solution and then finally extracted with dichloromethane. The organic phase is dried over MgSO4 and then evaporated under reduced pressure. The residue is taken up in ethyl acetate, which brings about precipitation of the final product. The crystals thus obtained are filtered off to give 80 mg (10%) of compound 48.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:12][CH2:13][CH2:14][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: ClCCCl
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Yield: 83.9 %

Procedure:
A slurry containing 2-amino-3-nitrophenol (32.0 g, 0.208 mol), 1,2-dichloroethane (260.0 g, 2.65 mol), potassium carbonate (35.0 g, 0.252 mol) and 2-butanone (750 mL) was refluxed for 24 hr. The mixture was cooled, filtered and the solids were washed with ethyl acetate. The filtrate was concentrated to an oily residue that was dissolved in ethyl acetate (500 mL). The organic layer was washed with 1 N sodium hydroxide (250 mL), water (500 mL), and brine (2×500 mL), dried over anhydrous magnesium sulfate. Concentration of the filtered solution and trtuation of the residue with hexane afforded 37.8 g (84.6%) of product as an orange solid, mp 71-73° C.; MS (+)PBEI m/e 216/218 (M+).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]/[C:28](OCC)=[O:29].CO.O.CCOCC>C1COCC1>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]/[CH2:28][OH:29]
Reactant: CCOC(=O)/C=C/CCCCCCCCOCOCCOC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCCOCOCCCCCCCC/C=C/CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 mmol of diisobutylaluminum hydride (DIBAH) (1.2 molar solution in toluene) are added with exclusion of moisture to a solution of 1 mmol of 3 in 20 ml of THF (abs.) at such a rate that the temperature does not exceed 40° C. The mixture is stirred at room temperature for 2 hours. Excess DIBAH is carefully hydrolyzed by means of methanol/H2O, the mixture is stirred for 20 minutes, and ether is added. The precipitate is filtered off with suction and washed several times with ether. The solution is dried over MgSO4, and the solvent is removed in vacuo. The product is purified by flash chromatography (PE/CH2Cl2)
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:27])[CH2:21][CH2:22][S:23]C(=O)C)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].CO>C(O)(=O)C>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:27])[CH2:21][CH2:22][SH:23])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)SCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(CCS)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
1.0 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-3-(acetylthio)propionamide [prepared as described in step (a) above] and 0.49 g of a 28% w/v methanolic solution of sodium methoxide were added to 20 ml of methanol, whilst ice-cooling, and the mixture was stirred at the same temperature for 20 minutes. At the end of this time, 0.15 ml of acetic acid was added, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and condensed by evaporation under reduced pressure, to obtain 0.76 g (yield 85%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=C)=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:7]=1)=[O:5])[CH3:2].C[N+]1([O-])CC[O:31]CC1.O.I([O-])(=O)(=O)=O.[Na+]>O1CCOCC1.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[O:31])=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:7]=1)=[O:5])[CH3:2]
Reactant: C=Cc1c(C(=O)OCC)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1C=O
Reaction time: 3.5 h

Procedure:
A solution of 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-vinyl-1H-pyrazole-3-carboxylic acid ethyl ester I-1b (2.9 g, 7.5 mmol), osmium tetroxide (8 mg, 0.08 mmol) and N-methylmorpholine-N-oxide (1.1 g, 8.2 mmol) in dioxane (24 ml)/water (6 ml) was stirred at ambient temperature for 18 hours, then sodium periodate (16 g, 75 mmol) was added and stirring was continued for 3.5 hours. The thick slurry was diluted with ethyl acetate (100 ml), filtered and solids washed 2× with ethyl acetate. The combined filtrates were washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford a solid mass. The solids were slurried in hot hexanes (30 ml), cooled, filtered and dried in vacuo to afford the title compound (I-1c) as a tan solid, 2.2 g.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[C:5]([CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH2:32]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C>[CH2:16]([NH:15][C:13]([C:4]1[S:3][C:2]([NH:1][C:43](=[O:44])[C:42]2[CH:41]=[CH:40][C:39]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:47][CH:46]=2)=[N:6][C:5]=1[CH2:7][N:8]([CH2:9][CH3:10])[CH2:11][CH3:12])=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Reactant: CCN(CC)Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(CC)Cc1nc(NC(=O)c2ccc(Cc3ccccc3)cc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.7 %

Procedure:
To a solution of 2-amino-N-benzyl-4-((diethylamino)methyl)thiazole-5-carboxamide (0.052 g, 0.16 mmol) and diisopropylethylamine (0.30 mL, 1.70 mmol) in dichloromethane (5 mL) was added 4-benzylbenzoic acid (0.046 g, 0.21 mmol) followed by the addition of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.076 g, 0.20 mmol). The reaction mixture was stirred at ambient temperature for 18 h, diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (acetone/water gradient) to afford the title compound (0.003 g); MS (ES+) m/z 513.