Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH2:3][N:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])=O.[NH:19]1[C:27]2[C:22](=[C:23]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+].[Cl:54]CCCl>O.C(O)(=O)C>[ClH:54].[NH:19]1[C:27]2[C:22](=[C:23]([N:28]3[CH2:33][CH2:32][N:31]([CH2:1][CH2:3][N:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:5]([CH:7]4[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]4)=[O:6])[CH2:30][CH2:29]3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: ClCCCl
Reactant: O=CCN(C(=O)C1CCCCC1)c1ccccn1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cl
Product: O=C(C1CCCCC1)N(CCN1CCN(c2cccc3[nH]ccc23)CC1)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.94 g of N-formylmethyl-N-(2-pyridyl)cyclohexanecarboxamide, 0.69 g of 1-(4-indolyl)piperazine, 1.21 g of sodium triacetoxyborohydride, 0.44 ml of acetic acid and 30 ml of 1,2-dichloroethane was stirred at room temperature for 3 h. Afterwards, it was diluted with 20 ml of water and alkalinized to pH=10 with 20% Na2CO3. The aqueous layer was extracted twice with 1,2-dichloroethane and the combined organic layers were dried (sodium sulfate) and evaporated to dryness in vacuo affording a crude which was purified by flash chromatography (methylene chloride-methanol 98:2 to 95:5) affording 0.96 g of the title compound as a base. This was dissolved in 40 ml of methylene chloride and to the solution was added 3.8 N hydrogen chloride in diethyl ether. The precipitated title compound was filtered, yielding 0.66 g. M.p. 181-7° C.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([CH2:25][CH2:26][S:27][CH3:28])[C:14]([O:16][C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])=[O:15].[P:29](Cl)(Cl)(=[O:41])[O:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.C(Cl)[Cl:45]>>[Cl:45][C:32]1[CH:33]=[CH:34][C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:31]=1[O:30][P:29](=[N:12][C@@H:13]([CH2:25][CH2:26][S:27][CH3:28])[C:14]([O:16][C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])=[O:15])=[O:41]
Reactant: ClCCl
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: CSCC[C@H](N)C(=O)O[C@@H](C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CSCC[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(=O)O[C@@H](C)c1ccccc1
Yield: 74 %

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates the tosylate salt of (S)-((S)-1-phenylethyl) 2-amino-4-(methylthio)butanoate (2.00 g, 4.70 mmol), naphthalene-1-yl phosphorodichloridate (1.23 g, 4.70 mmol) and TEA (1.31 mL, 9.40 mmol) in 30 mL of dry DCM, were combined to give (2S)-((S)-1-phenylethyl) 2-(chloro(naphthalen-1-yloxy)phosphorylamino)-4-(methylthio)butanoate in 74% yield (1.67 g), as a clear, yellow, thick oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[CH2:15]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[CH3:16].CC1C=CC(N=CC2C=C(OC)C(OC)=C(OC)C=2)=CC=1>>[CH2:15]([O:17][C:18]1[CH:24]=[CH:23][C:21]([N:22]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CCOc1ccc(N)cc1
Agent: COc1cc(C=Nc2ccc(C)cc2)cc(OC)c1OC
Product: CCOc1ccc(N=Cc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
From 3,4,5, trimethoxybenzaldehyde 106 (6.0 g, 30 mmol) and 4-ethoxyaniline 107d (4.1 g, 30 mmol), a similar procedure as described for 108a (5.9 g, 97.4%) as yellow crystals: mp 75°-7° C. after recrystallization from ethanol. 1H NMR (200 MHz, CDCl3) δ8.37 (s, 1H), 7.21 (d, J=8 Hz, 2H), 7.14 (s, 2H), 6.91 (d, J=8 Hz, 2H), 4.05 (q, J=6 Hz, 2H), 3.94 (s, 6H), 3.91 (s, 3H), 1.43 (t, J=6 Hz, 3H). EIMS m/e 315 (M+, 93).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:15])[CH:5]=[C:6]2[C:11]=1[N:10]=C(C(Br)Br)[CH:8]=[CH:7]2.[CH3:16][CH2:17][OH:18].[OH2:19]>CCO.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:3]=[C:4]([F:15])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:16]([C:17]([OH:19])=[O:18])[CH:8]=[CH:7]2
Reactant: O
Reactant: CCO
Reactant: Fc1cc(Br)c2nc(C(Br)Br)ccc2c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: O=C(O)c1ccc2cc(F)cc(Br)c2n1

Procedure:
8-Bromo-2-(dibromomethyl)-6-fluoroquinoline (17.2 g, 43.2 mmol) was weighed into a flask and dissolved in 250 mL of EtOH, followed by addition of silver nitrate (23.5 g, 138 mmol) in 100 mL of 1:1 EtOH/H2O. The reaction was heated to reflux for 1 hour, at which time all starting material had been consumed. The reaction was removed from heat and filtered hot through a medium frit scintered glass funnel, affording 5.84 g of 8-bromo-6-fluoroquinoline-2-carboxylic acid as a white/yellow powder. The mother liquor was concentrated in vacuo, followed by extractive work-up (200 mL ethyl acetate/water). The combined organics were dried over Na2SO4 and concentrated in vacuo to afford the desired products as an orange-brown semi solid (99% overall; 6.4 g and 5.8 g respectively). MS APCI (+) m/z 298 and 300 (M+1 of each isotope) detected; MS APCI (−) m/z 268 and 269.9 (M−1 of each Br isotope) detected.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH2:7][CH3:8].II.[I:31](O)(=O)=O>O.C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH2:6]([C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:16][CH2:17][C@H:18]([CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([I:31])=[CH:27][CH:28]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)[CH2:7][CH3:8]
Reactant: [O-][I+2]([O-])O
Reactant: CCCc1ccc([C@H]2CC[C@H](CCc3ccccc3)CC2)cc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCCc1ccc([C@H]2CC[C@H](CCc3ccc(I)cc3)CC2)cc1

Procedure:
To a liquid mixture comprising 50 ml of acetic acid, 5 ml of carbon tetrachloride, 5 ml of concentrated sulfuric acid, and 10 ml of water, were added 5.8 g of the (2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)benzene mentioned above, 2.4 g of iodine, and 2 g of iodic acid, and they were stirred under a reflux for 2 hours. After cooled, the mixture was washed with a saturated aqueous solution of sodium thiosulfate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain a yellow-brown oily product. This product was purified by a column chromatography over an alumina by using heptane as an eluent, and further recrystallized from heptane to obtain 5.8 g of 4-(2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)iodobenzene.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38]N>>[CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[C:34]4[C:33](=[C:32]([CH3:31])[CH:37]=[CH:36][CH:35]=4)[NH:38][C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]phenyl}propanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 480.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4].[S:11](Cl)(Cl)=[O:12].[CH:15]1([NH:21][P:22](=[S:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>N1C=CC=CC=1>[CH2:24]([O:23][P:22]([N:21]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[S:11]([CH2:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4])=[O:12])([O:26][CH2:27][CH3:28])=[S:29])[CH3:25]
Reactant: CNC(=O)ON=C(C)SC
Reactant: CCOP(=S)(NC1CCCCC1)OCC
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCOP(=S)(OCC)N(C1CCCCC1)S(=O)CNC(=O)ON=C(C)SC

Procedure:
Methyl N-[[[[[(diethoxyphosphinothioyl)cyclohexylamino]sulfinyl]methylamino]carbonyl]oxy]ethanimidothioate was prepared by the procedure employed in Example 9, by reacting methyl N-[[(methylamino)carbonyl]oxy]ethanimidothioate (2.43 g, 0.015 mole), thionyl chloride (1.79 g, 0.015 mole) and O,O-diethyl cyclohexylphosphoramidothioate (3.77 g, 0.015 mole) in pyridine 10 ml. Recrystallization from chloroform-hexane afforded 2.5 g of colorless prisms of the formula below, mp 72~74°. ##STR31##
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH:11]([NH2:14])([CH3:13])[CH3:12].[Cl:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>>[Cl:15][CH2:16][CH2:17][NH:18][C:19]([N:14]([CH:11]([CH3:13])[CH3:12])[CH:9]1[O:10][CH2:2][C@H:3]([OH:4])[C@H:5]([OH:6])[C@H:7]1[OH:8])=[O:20]
Reactant: CC(C)N
Reactant: O=C=NCCCl
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Product: CC(C)N(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 70.8 %

Procedure:
3.0 g of L-arabinose, 2.5 g of isopropylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 4.2 g of 1-(2-chloroethyl)-3-isopropyl-3-L-arabinopyranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: [NH2:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.[Br:35][C:36]([Br:41])([CH2:39][Br:40])[CH:37]=O.CN(C)C1C=CC=CC=1.S(Cl)(Cl)=O.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl>[Br:35][C:36]([Br:41])([CH2:39][Br:40])[CH:37]=[N:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=CC(Br)(Br)CBr
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N=CC(Br)(Br)CBr)[C@H]2SC1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
To a solution of benzhydryl 7β-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (2.473 g, 5.000 mmol) in methylene chloride (35 ml) was added under ice-cooling a solution of 2,2,3-tribromopropanal (1.474 g, 5.000 mmol) in methylene chloride (5 ml) and the mixture was stirred for 20 minutes. The reaction mixture was cooled to -20° C., N,N-dimethylaniline (3.5 ml) was added thereto and then thionyl chloride (0.5 ml, 6.9 mmol) was added dropwise. After stirring under ice-cooling for 2 hours, the reaction mixture was poured into a mixture of a saturated aqueous solution of potassium hydrogen sulfate (100 ml) with ice (100 g) followed by extraction with methylene chloride (400 ml, twice). The methylene chloride layer was washed successively with an ice-cooled saturated aqueous solution of potassium hydrogen sulfate (200 ml) and then ice-water (200 ml). Thereafter, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized with the addition of ethyl acetate (20 ml). The crystalline substance was recovered by filtration, washed with a small volume of ice-cooled methylene chloride and dried under reduced pressure to yield 2.720 g (71%) of the title compound as a pale yellow crystal. This product gradually decomposed with coloration at 90° C. and higher.
Reaction SMILES: C[N:2](C)C=O.P(Cl)(Cl)(Cl)=O.[C:11]([CH2:14][O:15][CH2:16][C@@H:17]1[CH2:21][C@@H:20]([OH:22])[CH2:19][N:18]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(O)=[O:12].O.N>O1CCCC1>[C:11]([CH2:14][O:15][CH2:16][C@@H:17]1[CH2:21][C@@H:20]([OH:22])[CH2:19][N:18]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(=[O:12])[NH2:2]
Reactant: O=C(O)COC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=O
Agent: N
Solvent: C1CCOC1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: NC(=O)COC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a mixture of dimethylformamide (1.50 ml) and tetrahydrofuran (10 ml) was dropwise added phosphorus oxychloride (1.50 ml) at -5°~5° C. and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added a solution of (2S,4R)-2-carboxymethyloxymethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.30 g) in tetrahydrofuran (20 ml) at -5°~5° C., followed by stirring at the same temperature for 30 minutes. The mixture was dropwise added to concentrated ammonia water (30 ml) at 0°-10° C. with stirring. The mixture was stirred at the same condition for 2 hours. Tetrahydrofuran was evaporated under reduced pressure to give a mixture. The mixture was extracted with ethyl acetate (50 ml×3). The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (3:97 V/V) to give (2S,4R)-2-(carbamoylmethyloxymethyl)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.43 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:21])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[C:22](=[O:25])(O)[O-:23].[Na+]>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([NH:20][C:22](=[O:25])[O:23][C:4]([CH3:15])([CH3:5])[CH3:3])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:21])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: NC1=NC2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.770 g, 1.624 mmol; prepared as described in Method BB26) was dissolved in dioxane (8 mL). 8 mL of saturated sodium bicarbonate solution was added, followed by boc-anhydride (3.77 mL, 16.24 mmol). The reaction was stirred overnight at RT. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (gradient elution 0-25% EtOAc:Hex) to afford tert-butyl 3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate as a yellow solid. MS m/z=576.0. Calc'd for C19H17BrIN3O3S: 574.23.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(Cl)Cl.[C:17]1([N:23]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:17]1([N:23]2[CH2:27][CH2:26][CH:25]([NH:28][C:8](=[O:9])[C:7]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC1CCN(c2ccccc2)C1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCN(c2ccccc2)C1)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of 6.9 g. (0.037 mole) of p-nitrobenzoyl chloride in 30 ml. of chloroform was added dropwise at room temperature to a stirred mixture of 6 g. (0.037 mole) of 1-phenyl-3-aminopyrrolidine in 30 ml. of chloroform and 10 g. of potassium carbonate in 30 ml. of water. After addition, the mixture was stirred an additional 30 minutes. The chloroform layer was separated, dried over magnesium sulfate and evaporated to a solid. Recrystallization of the crude product from ethanol-water solution gave 10.6 g. (92%) of orange solid which melted at 153°-155°C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])#[N:2].C1CCCCC=1>CO.[Pd]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([N:12]=[CH:13][N:14]([CH3:15])[CH3:16])=[C:3]([C:1]#[N:2])[CH:8]=1
Reactant: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CO
Product: CN(C)C=Nc1ccc(N)cc1C#N

Procedure:
A solution of 6.0 g (27.5 mmol) of N'-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine, 33.9 g (41.8 ml, 412.4 mmol) of cyclohexene, and 0.6 g of 10% Pd/C in 360 ml of methanol was refluxed for 4 hrs. The hot mixture was filtered through Celite. Solvent was removed and the residue was recrystallized from chloroform-carbon tetrachloride giving 4.9 g (95%) of the tide compound as a light gray crystalline solid. mass spectrum (m/e): 188.9 (M+H, electrospray).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[CH3:16][N+:17]([O-:19])=[O:18]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:10][CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: COCCOCOc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: COCCOCOc1ccc(/C=C/[N+](=O)[O-])cc1
Yield: 79 %

Procedure:
A mixture of 4-((2-methoxyethoxy)methoxy)benzaldehyde (Intermediate I, 1.86 g, 8.85 mmol) and NH4OAc (0.75 g, 9.73 mmol) in dry THF (15 mL) and CH3NO2 (15 mL) was refluxed for 20 h and allowed to reach room temperature. The volume of the reaction was reduced to approx. ⅓, by rotatory evaporation; the resulting solution was poured into water (15 mL) and extracted with AcOEt (2×15 mL). The organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residual brown oil was purified by column chromatography on silica gel (15-30% EtOAc/Hexanes) affording 1.77 g of (E)-1-((2-methoxyethoxy)methoxy)-4-(2-nitrovinyl)benzene [Rf=0.7 (50% AcOEt/Hexanes), yellow solid, 79% yield].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:22]12([CH2:32][CH2:33]O)[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[C:22]12([CH2:32][CH2:33][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]3[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:16][N:15]=3)[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]3)[CH2:31]1)[CH2:29]2
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCCC12CC3CC(CC(C3)C1)C2
Yield: 75 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 1-adamantaneethanol (27 mg, 0.15 mmol) as the coupling partner. Concentration (no chromatography) yielded 58 mg (75%) of the titled compound. ESI-MS m/z 454 (MH+), 452 (M−H−).
Reaction SMILES: [CH3:1][O:2][C:3]([C:12]1[CH:17]=[C:16]([C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH:15]=[C:14]([C:28]([O:37][CH3:38])([C:33]([F:36])([F:35])[F:34])[C:29]([F:32])([F:31])[F:30])[CH:13]=1)([C:8]([F:11])([F:10])[F:9])[C:4]([F:7])([F:6])[F:5].C(Cl)(=[O:42])C=C>>[C:18]([OH:27])(=[O:42])[CH:16]=[CH2:17].[CH3:38][O:37][C:28]([C:14]1[CH:15]=[C:16]([C:18]([OH:27])([C:23]([F:24])([F:25])[F:26])[C:19]([F:20])([F:21])[F:22])[CH:17]=[C:12]([C:3]([O:2][CH3:1])([C:4]([F:5])([F:6])[F:7])[C:8]([F:9])([F:10])[F:11])[CH:13]=1)([C:29]([F:32])([F:31])[F:30])[C:33]([F:36])([F:35])[F:34]
Reactant: C=CC(=O)Cl
Agent: COC(c1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C(OC)(C(F)(F)F)C(F)(F)F)c1)(C(F)(F)F)C(F)(F)F
Product: C=CC(=O)O
Reaction time: 2 h

Procedure:
A solution of 14.00 g (0.232 mole) 1,3-bis-(2-methoxyhexafluoro-5-(2-hydroxyhexafluoro-2-propyl)-benzene (II) in 40 ml of Freon 113 was stirred magnetically in a 200 ml 3-neck flask equipped with a dropping funnel, thermometer, dry ice-acetone condenser and drying tube (CaCl2). 24.6 g of triethylamine dissolved in 15 ml of Freon 113 was added dropwise during 20 minutes with slight exotherm. An external cooling bath (ice water) was applied. Then a second dropping funnel charged with 2.20 g (0.024 mole) of acryloyl chloride (III) dissolved in 15 ml of Freon 113 was quickly substituted in place of the empty funnel. The latter charge was added during 30 minutes at 10°-20° C. After stirring an additional 2 hours, the resulting white slurry was vacuum filtered (60 ml C filter - 3 g of Celite cake). Flash evaporation of the filtrate left 15.5 g of honey-like residue that readily crystallized (mp 58°-62° C.) and analyzed 80 mole % diether acrylate (IV), 17% unreacted diether ol (II), and 3% acrylic anhydride. Trituration of this mixture in 100 ml of a 2% sodium hydroxide solution followed by neutralization led to 13.1 g of white crystals (mp 61°-62° C.) analyzing 90.6% (IV) and 9.4% (II), with no acrylic anhydride. The 13.1 g of crude ester was submitted again to the customary esterification procedure using 1.21 g of triethylamine and 1.07 g of acryloyl chloride. This led to 12.9 g of crystals analyzing 94.3 mole % (IV) and 5.7% acrylic anhydride. Workup in 2% sodium hydroxide solution led to 12.6 g of white crystals (mp 65°-66° C.) of 100% purity (IV) by GLC. Recrystallization from petroleum ether at -70° F. (-57° C.) gave 11.7 g analytical (IV) as extremely water repellent white crystals; 76.7% yield; mp 66° C. By analysis as calculated for C20H12F18O4 : C, 36.49; H, 1.84; F, 51.95; as found: C, 36.58; H, 1.79; F, 51.96.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13].[N+:25]([C:28]1[CH:38]=[CH:37][C:31]([CH2:32][O:33][C:34](Cl)=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26].[OH-].[Na+]>O.O1CCCC1>[OH:11][C@H:9]1[CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[C@H:6]([C:2]2[N:1]([C:34]([O:33][CH2:32][C:31]3[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:38][CH:37]=3)=[O:35])[CH:5]=[CH:4][N:3]=2)[CH2:10]1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1c1ncc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1c1nccn1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 63 %

Procedure:
To a solution of (2S,4R)-2-(imidazol-2-yl)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.0 g) in a mixture of water (10 ml) and tetrahydrofuran (20 ml) was dropwise added a solution of 4-nitrobenzyloxycarbonyl chloride (0.85 g) in tetrahydrofuran (5 ml) under ice-cooling with stirring, keeping the pH between 9 and 10 with 4N aqueous sodium hydroxide. The mixture was stirred under the same condition for 1 hour, extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give (2S,4R)-4-hydroxy-2-[N-(4-nitrobenzyloxycarbonyl)imidazol-2-yl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (970 mg).