Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:35]=[C:34]3[O:36][CH2:37][C:31]4[C:32]5[C:33]3=[C:24]([CH2:25][O:26][C:27]=5[CH:28]=[C:29]([C:38]3[NH:42][C:41]([C@@H:43]5[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]5[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[N:40][CH:39]=3)[CH:30]=4)[CH:23]=2)=[CH:20][N:21]=1)=O)C1C=CC=CC=1.[CH3:58][O:59][C:60]([NH:62][C@@H:63]([CH:67]([CH3:69])[CH3:68])[C:64](O)=[O:65])=[O:61].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.CCOC(C)=O.[Pd]>[CH3:58][O:59][C:60]([NH:62][C@@H:63]([CH:67]([CH3:69])[CH3:68])[C:64]([N:11]1[C@@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:35]=[C:34]3[O:36][CH2:37][C:31]4[C:32]5[C:33]3=[C:24]([CH2:25][O:26][C:27]=5[CH:28]=[C:29]([C:38]3[NH:42][C:41]([C@@H:43]5[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]5[C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])=[N:40][CH:39]=3)[CH:30]=4)[CH:23]=2)=[CH:20][N:21]=1)=[O:65])=[O:61]
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7CC[C@H](C)N7C(=O)OCc7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reaction time: 2 h
Yield: 58.5 %

Procedure:
(2S,4S)-tert-butyl 2-(5-(7-(2-((2S,5S)-1-(benzyloxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (300 mg, 0.38 mmol) 10 mL ethanol, and 19 mg 10% Pd/C was stirred under an atmosphere of hydrogen (balloon) overnight. Filtration through celite and concentration afforded the crude amine. The crude amine was dissolved in DMF (4 mL) and then (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (66 mg, 0.38 mmol), HATU (160 mg, 0.42 mmol) and N-methylmorpholine (0.084 mL, 0.76 mmol) were added. After 2 h, the reaction was diluted with EtOAc and washed successively with saturated aqueous NaHCO3, 5% LiCl, and brine. The organic phase was dried over Na2SO4, concentrated, and purified by silica gel chromatography (1% to 20% MeOH/EtOAc) to afford (2S,4S)-tert-butyl 2-(5-(7-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (177 mg, 58%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]([NH:14][C:15](=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2)([O:3]C)=[O:2].[OH-].[K+].CO>O1CCCC1.O>[C:1]([C:5]1[CH:13]=[C:12]([NH:14][C:15](=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2)([OH:3])=[O:2]
Reactant: CCCCCCCCCC(=O)Nc1cc(C(=O)OC)c2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCCCCCCC(=O)Nc1cc(C(=O)O)c2cc[nH]c2c1
Temperature: 80 °C
Yield: 60.7 %

Procedure:
Five hundred-fifteen mg of 4-carbomethoxy-6-(N-decanoylamino)indole [prepared by the method of Wender et al., PNAS, 83, 4214-4218 (1986)] was dissolved in 60 mL of tetrahydrofuran. This solution was treated with 3 mL of a 1N KOH solution in water and also with 5 mL of methanol. The mixture was heated at 80° C. for 32 h. During this period another 2.5 mL of 1N KOH was added in two portions. After cooling the mixture was concentrated in vacuo. The mixture was then diluted with water and acidified with concentrated hydrochloric acid. The mixture was then extracted with methylene chloride. The organic layers were dried over sodium sulfate and concentrated to afford 300 mg of 4-carboxy-6-(N-decanoylamino)indole (60% yield), mp 248°-50° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]1
Reactant: CCOC(=O)CCN1CCC(CNC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCN1CCC(CN)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 3-(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)propanoate (500 mg, 1.6 mmol, step 1 of Example 10) in CH2Cl2 (5 mL), trifluoroacetic acid (1.2 mL, 16 mmol) was added and stirred overnight at room temperature. The mixture was concentrated, and the residual oil was dissolved in CH2Cl2 (60 mL) and solid K2CO3 (5 g) was added, and stirred for 10 min. The mixture was filtered, and the filtrate was concentrated to give ethyl 3-[4-(aminomethyl)piperidin-1-yl]propanoate as a pale yellow oil. Following coupling reaction was carried out according to the procedure described in step 6 of Example 1 from 3,3-dimethyl-1,3-dihydro-2H-indol-2-one (Robertson, David W et al., J. Med. Chem., 1986, 29, 1832) and ethyl 3-[4-(aminomethyl)piperidin-1-yl]propanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:18])([CH3:17])[CH2:9][CH:10]([OH:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:3]=1[O:19][CH3:20].CS(C)=O.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH2:14]([O:13][C:11](=[O:12])[C:10](=[O:16])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:19][CH3:20])[CH:4]=1)([CH3:18])[CH3:17])[CH3:15]
Reactant: CCOC(=O)C(O)CC(C)(C)c1ccc(Cl)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C(=O)CC(C)(C)c1ccc(Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.15 g (20.45 mmol) of ethyl 4-(4-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-pentanoate is dissolved in 213 ml of dichloromethane and mixed with 71 ml of dimethyl sulfoxide. After 10.3 g (102.23 mmol) of triethylamine is added, the batch is mixed in portions with 8.1 g (51.12 mmol) of SO3/pyridine complex and then stirred overnight at room temperature. While being cooled slightly, the reaction mixture is mixed with 81 ml of saturated ammonium chloride solution and vigorously stirred. After 2× extraction with diethyl ether, the combined organic phases are treated as usual. The residue that remains after the solvent is spun off is chromatographed on silica gel (mobile solvent ethyl acetate/hexane) together with the residue that results from another batch (15.27 g). 15.46 g (72.9%, from the two batches) of the desired compound is isolated.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([OH:6])([CH3:5])[CH3:4].[H-].[Na+].[N+]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)([O-])=O>CN(P(N(C)C)(N(C)C)=O)C.C(OCC)C>[F:1][C:2]([F:8])([F:7])[C:3]([CH3:5])([CH3:4])[O:6][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(Oc1ccc(C#N)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 25.2 %

Procedure:
Add 2-trifluoromethyl-2-propanol (3.4 g, 27 mmol) slowly to a slurry of sodium hydride (0.6 g, 60% in mineral oil, washed with hexane) in HMPA (5 mL) under nitrogen. Stir the slurry for 15 min and add a solution of 4-nitrobenzonitrile (2.0 g, 13.5 mmol) in HMPA (10 mL). Stir the resulting purple slurry at ambient temperature for 16 h, dilute with diethyl ether (100 mL) and wash with 5% aqueous HCl (30 mL). Separate the layers and extract the aqueous layer with diethyl ether (2×50 mL). Combine the organic extracts and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) to obtain the desired intermediate (780 mg, 25%). GC-MS m/z: 229 (M+).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[CH3:12][C:13]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH2:16][C:17]1[NH:18][CH2:19][CH2:20][N:21]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)(Cl)Cl.C(OCC)C>[C:28]1([NH:27][C:1]([N:21]2[CH2:20][CH2:19][N:18]=[C:17]2[CH2:16][O:15][C:14]2[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:13]=2[CH3:12])=[O:2])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccccc1
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(OCC2=NCCN2C(=O)Nc2ccccc2)c1C
Reaction time: 2 h

Procedure:
A 17% solution of phosgene in toluene (3.2 g containing 0.5521 g., 0.00549 moles COCl2) in dry chloroform (15 ml) was added slowly with stirring at 0° C. to a solution of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline (2.40 g, 0.0115 moles) in dry chloroform (20 ml). When addition was complete the reaction mixture was left at ambient temperature for 2 hours, diluted with an equal volume of dry diethylether and rapidly filtered. The filtrate, which contained the N-chlorocarbamoyl adduct of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline, was treated with freshly distilled dry aniline (0.664 g, 0.00714 moles) and the mixture left at ambient temperature overnight at which time tlc showed that the major compound was the desired product. The mixture was evaporated to dryness in vacuo and the residue taken up in a mixture of aqueous sodium carbonate and dichloromethane. The organic layer was washed with water, dried over magnesium sulphate and evaporated to dryness to give a residue which was purified as described in (A) above to give 1-N-phenylcarbamoyl-2-(2,3-dimethylphenoxymethyl)-2-imidazoline, identical with that obtained in (A) above.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(Cl)c3)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (3-chloro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=427.1 (M+H)+
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2Cl)=[N:13][C:12]([Cl:17])=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.[CH3:18][N:19]([CH3:27])[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]1>>[Cl:17][C:12]1[N:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])=[C:15]2[NH:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([N:19]([CH3:27])[CH3:18])[CH2:21][CH2:22]1
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Reactant: O=C(c1cnc2ccc(Cl)nc2c1Cl)C1CC1
Product: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Cl)nc23)CC1

Procedure:
Following general procedure I, cyclopropyl(4,6-dichloro-1,5-naphthyridin-3-yl) methanone (243 mg, 0.91 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine (168 mg, 1.2 mmol) to afford the desired product (150 mg, 44%) as a light yellow solid. 1H NMR (500 MHz, Chloroform-d) δ 10.83 (br s, 1H), 9.20 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 4.98 (br s, 1H), 2.71-2.63 (m, 1H), 2.33 (s, 6H), 2.34-2.29 (m, 2H), 2.28-2.19 (m, 1H), 2.06-1.97 (m, 2H), 1.54-1.33 (m, 4H), 1.31-1.22 (m, 2H), 1.11-1.01 (m, 2H). ESI MS m/z 373 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[H-].[Na+].[H][H].[Br:17][C:18]1[C:19](Cl)=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1>C1COCC1>[Br:17][C:18]1[C:19]([O:1][CH:2]2[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]2)=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1
Reactant: [H][H]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2nc(Cl)ncc2Br)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.4 %

Procedure:
To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (4.1 g, 23.7 mmole) in anhydrous THF (100 mL) at 0° C. was added NaH (60% in mineral oil, 1.33 g, 33.2 mmol). The mixture was stirred at 0° C. for 4 5 min and then room temperature for 2 h until there was no hydrogen bubbles generated. This mixture was added slowly to a solution of 5-bromo-2,4-dichloropyrimidine (10.8 g, 47.4 mmol) in THF (100 mL) at −20° C., and then the reaction mixture was stirred at the same temperature for 2 h and then at room temperature for 3 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was purified using flash chromatography (silica gel, 5-10% EtOAc in hexanes) to give the title compound (6 g, 70% yield) as a white solid. MS (ESI) m/z: Calc. 363.0 (M+). Found: 309.1 (M++2-tButyl).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([O:10][Si](C(C)C)(C(C)C)C(C)C)[C:7]([CH3:21])=[CH:6][C:3]=1[CH:4]=O.Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH:31]([CH3:33])[CH3:32])[C:24]=1[CH3:34]>>[CH3:21][C:7]1[CH:6]=[C:3]([CH2:4][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH:31]([CH3:32])[CH3:33])[C:24]=2[CH3:34])[C:2]([CH3:1])=[CH:9][C:8]=1[OH:10]
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(C)cc1C=O
Reactant: COc1ccc(Br)c(C)c1C(C)C
Product: COc1ccc(Cc2cc(C)c(O)cc2C)c(C)c1C(C)C

Procedure:
Intermediate 2,5-dimethyl-4-(4′-methoxy-2′-methyl-3′-iso-propyl-benzyl) phenol was prepared from 2,5-dimethyl-4-triisopropylsilanyloxy-benzaldehyde and 1-bromo-4-methoxy-2-methyl-3-iso-propylbenzene according to the procedure described in Chiellini et al., Bioorg. Med. Chem. Lett. 10:2607 (2000) and transformed into the title compound by the procedure described for the synthesis of compound 7: 1H NMR (300 MHz, DMSO-d6): δ 6.93 (s, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.64 (s, 1H), 4.09 (d, J=9.9 Hz, 2H), 3.79 (s, 2H), 3.77 (s, 3H), 3.34 (m, 1H), 2.22 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.31 (d, J=7.2 Hz, 6H); LC-MS m/z=391 [C21H29O5P−H]−.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][C:6]3[C:11]([CH:2]12)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(#N)C>[OH:1][C@@H:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C@H:2]1[N:22]1[CH2:23][CH2:24][CH2:25][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20][CH2:21]1
Reactant: c1ccc2c(c1)CCC1OC21
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCN([C@@H]2c3ccccc3CC[C@H]2O)CC1

Procedure:
At ambient temperature, 3.0 g (20.5 mmol) of the compound obtained in Step B of Example 15 and 4.1 g (20.5 mmol) of N-tert-butyloxycarbonyl-homopiperazine in 41 ml of acetonitrile are mixed together and then heated at reflux for 48 hours. After evaporation and flash chromatography on 300 g of silica (eluant: dichloromethane/ethanol 98/2), the expected compound is collected.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=O)[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1.[O:18]([C@@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([OH:23])=[O:22])[NH2:19].CO.Cl>C(OCC)(=O)C.N1C=CC=CC=1>[OH:1][C@@H:2]1[CH2:6][C:5](=[N:19][O:18][CH:20]([C:21]([OH:23])=[O:22])[CH2:24][CH:25]([CH3:27])[CH3:26])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1.[OH:1][C@H:2]1[CH2:6][C:5](=[N:19][O:18][CH:20]([C:21]([OH:23])=[O:22])[CH2:24][CH:25]([CH3:27])[CH3:26])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1
Reactant: COC(=O)CCCCCCC1=CC(O)CC1=O
Reactant: CC(C)C[C@H](ON)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)CCCCCCC1=C[C@@H](O)CC1=NOC(CC(C)C)C(=O)O
Product: COC(=O)CCCCCCC1=C[C@H](O)CC1=NOC(CC(C)C)C(=O)O
Reaction time: 16 h

Procedure:
A mixture consisting of 0.240 part of methyl 3(RS)-hydroxy-5-oxocyclopent-1-eneheptanoate, 0.200 part of 2(S)- aminoxyisocaproic acid and 4 parts of methanol is treated with 0.5 part of pyridine. That mixture is allowed to stand at room temperature for about 16 hours and then is poured into 45 parts of ethyl acetate and 20 parts by volume of 0.5 N hydrochloric acid. The ethyl acetate layer is separated, washed with water and dried over anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is chromatographed on silica gel using 1% ethyl acetate in chloroform as eluent to afford successive fractions of methyl 3(R)-hydroxy-5[(1-carboxyisoamyl)oxyimino]cyclopent-1-eneheptanoate, melting at about 62°-63° and methyl 3(S)-hydroxy-5-[(1-carboxyisoamyl)oxyimino]cyclopent-1-eneheptanoate.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O.C([N:20](C(C)C)CC)(C)C.N[N:27]([CH:35]=[NH:36])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[NH:20]=[C:35]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:36][C:11](=[O:13])[C:10]([O:9][C:2]1[C:1]([CH3:16])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=1[CH3:8])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(N)C=N
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C)c(OC(C)(C)C(=O)O)c(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(OC(C)(C)C(=O)NC(=N)NC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 41 h
Yield: 66.3 %

Procedure:
2-(Mesityloxy)-2-methylpropionic acid (4.45 g; 20 mmol), diisopropylethylamine (12.93 g; 100 mmol), tert-butyl amino(imino)methylcarbamate (3.82 g; 24 mmol), and 1-hydroxybenzotriazole monohydrate (3.68 g; 24 mmol) were dissolved in N,N-dimethylformamide (100 mL), 2-(1H)-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate (9.10 g; 24 mmol) was added, and the mixture was stirred for 41 hours at room temperature. To the reaction solution, ethyl acetate (300 mL) was added, and the mixture was washed with 10% aqueous citric acid solution, brine, saturated aqueous sodium bicarbonate solution, and then brine. The organic layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure. The resulting crystals were dispersed in diisopropyl ether, collected by filtration and dried to give 4.82 g of the title compound (yield 66%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:25])[N:10]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24])[C:11]2=[O:16])=[O:4].[N-:26]=[N+:27]=[N-:28].[Na+].[I-].[Na+]>CC(C)=O>[N:26]([CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:25])[N:10]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24])[C:11]2=[O:16])=[O:4])=[N+:27]=[N-:28]
Reactant: O=C(CCl)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 90.8 %

Procedure:
A mixture of 2-chloro-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}acetamide (1.3 g, 3.57 mmol), sodium azide (0.3 g, 4.65 mmol) and sodium iodide (0.54 g, 3.57 mmol) in acetone (50 ml) was refluxed for 17 hours. The solvent was removed in vacuo and the residue was dissolved in EtOAc (60 ml). The EtOAc solution was washed with H2O (30 ml), brine (30 ml), and dried (MgSO4). The solvent was removed in vacuo to give 2-azido-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}acetamide (1.2 g, 90%) as a white solid: 1H NMR (CDCl3) δ d 8.48 (s, 1H), 7.84-7.68 (m, 3H), 7.51 (t, J=6.3 Hz, 1H), 5.04-4.97 (dd, J=4.7 and 11.8 Hz, 1H), 4.80 (d, J=6.5 Hz, 2H), 3.97 (s, 2H), 2.95-2.74 (m, 3H), 2.20-2.15 (m, 1H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>CCCCCC>[CH2:8]([O:7][C:1](=[O:6])[CH:2]=[C:3]([O:4][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH3:5])[CH3:9]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)C=C(C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of 31.9 mL (0.25 mole) of ethyl acetoacetate is stirred in hexane (350 mL) at room temperature. Triethylamine (42 mL, 0.30 mole) is added, followed by dropwise addition of trimethylsilyl chloride (35 mL, 0.276 mole) keeping the internal temperature below 25° C. using a water bath (about 18° C.). The thick white slurry is stirred overnight at room temperature. 200 mL of hexane is then added and the mixture stirred in an ice bath for 1 hour. The mixture is filtered and the solids are washed with 50 mL of cold hexane. Evaporation of the combined filtrate and washings gives 46 g of 3-trimethylsilanyloxy-but-2-enoic acid ethyl ester as a colorless, slightly cloudy oil. This material is used without further purification in the following step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].CN(C=[O:19])C.C(N(CC)CC)C.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29]>O.C(OC)(C)(C)C>[C:9]([OH:14])(=[O:19])[CH:10]=[CH2:11].[C:27]([OH:30])(=[O:1])[CH:28]=[CH2:29].[CH:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC(=O)Cl
Reactant: CN(C)C=O
Reactant: Oc1ccccc1-c1ccccc1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: COC(C)(C)C
Product: C=CC(=O)O
Product: c1ccc(-c2ccccc2)cc1

Procedure:
To a 1000 ml 3 neck round bottom equipped with an overhead stirrer and temperature probe was added 2,2′-dihydroxy-biphenyl (50 g), Prostab 5198 (0.02 g), DMF (150 ml) and triethylamine (59.8 g). The reaction was cooled to <0 C with methanol/dry ice bath and acryloyl chloride (51 g) was slowly added. The GC indicated the reaction was mostly complete with ˜15% monoacrylate. Triethylamine (10 g) was added followed by the addition of acryloyl chloride (9 g). The GC indicated the reaction was complete. The reaction product was treated with (300 ml) methyl t-butyl ether and (300 ml) DI water. The organic portion was separated and washed 5 times with 200 ml sodium chloride brine. The organic portion was treated with 50 g filter aid, mixed and filtered through a thin pad of silica gel. The filtrate was concentrated in vacuo to recover a yellow oil. This oil (69 g) was taken up in 300 ml chloroform and filtered through a short silica gel column (5.5 inch diameter by 4 inches thick) and eluted with chloroform/heptane. The product (52 g) was recovered by concentrating the eluent in vacuo. GC indicated >98% product. The refractive index of the (i.e. uncured) monomer was determined to be 1.571.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:14]=[C:15]([S:18](=[O:21])(=[O:20])[NH2:19])[C:16]=1Cl)[C:9]([O:11]CC)=[O:10])[CH2:2][CH2:3][CH3:4].[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1([S-])C=CC=CC=1.[Na+]>C(O)C>[CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:14]=[C:15]([S:18](=[O:20])(=[O:21])[NH2:19])[C:16]=1[S:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Cl
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [S-]c1ccccc1
Solvent: CCO
Product: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccccc1

Procedure:
A mixture of ethyl 3-butylthio-4-chloro-5-sulfamylbenzoate (0.85 g), thiophenol (0.6 ml), and dry ethanol (25 ml) containing 5 millimoles of sodium thiophenolate is refluxed for 6 hours. After evaporation in vacuo 1 N sodium hydroxide (20 ml) and ethanol (10 ml) are added, and the mixture is refluxed for 15 minutes. After cooling and extraction with diethyl ether, 3-butylthio-4-phenylthio-5-sulfamylbenzoic acid is precipitated from the aqueous layer by addition of 4 N hydrochloric acid. The precipitate is collected by filtration and recrystallized from aqueous ethanol to yield the desired acid having a melting point of 192° - 193° C.