Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])=[CH:22][CH:21]=1>C1COCC1>[ClH:10].[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:14]([NH:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[NH:17])=[CH:22][CH:21]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCc1ccc(CO)cc1
Agent: I
Solvent: C1CCOC1
Product: Cl
Product: N=C(NCCCCc1ccc(CO)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Yield: 194 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl-2-methyl-pseudothiourea hydroiodide (0.2 g, 0.52 mmol) was added to an anhydrous THF suspension (20 mL) of 67 (0.37 g, 2.06 mmol). The reaction mixture was stirred at reflux for 3 h then the solvent was evaporated. The residue was washed with ethyl acetate (3×15 mL), dried and treated with 3% HCl (15 mL). The yellow solid that formed was filtered, washed with water (2×10 mL) and dried to provide 68 (216 mg, 98%). 1H NMR (300 MHz, DMSO-d6) δ 1.57 (br s, 4H), 2.62 (m, 2H), 3.35 (m, 2H), 3.73 (br s, 4H), 4.45 (s, 2H), 7.12 (d,-z2H), 7.24 (d, 2H), 8.85 (br s, 1H), 9.98 (br s, 1H), 9.32 (br s, 1H), 10.55 (s, 1H). APCI MS m/z 392 [C17H22ClN7O3+H]+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@:10]1([CH:50]1[CH2:52][O:51]1)[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:54]>CO.O1CCCC1>[NH2:54][CH2:52][CH:50]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:51]
Reactant: [NH4+]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@@](C5CO5)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(O)CN)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(oxiran-2-yl)-6,8-dioxabicyclo[3.2.1]octane 10a (0.4 g, 0.56 mmol) in a methanol/tetrahydrofuran mixture (v/v=1/2, 9 mL) was added ammonium hydroxide (2 mL, 10 mmol). The mixture was heated to 55° C. and stirred for 16 hours. The resulting mixture was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=6/1 to give the title compound 10b as colourless oil (0.21 g, 51.2%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.48 (m, 2H), 7.40 (m, 1H), 7.33 (m, 4H), 7.26 (m, 6H), 7.18 (m, 3H), 7.05 (m, 2H), 7.04 (m, 2H), 6.85 (m, 2H), 4.90 (m, 1H), 4.77 (m, 3H), 4.26 (d, 1H), 4.11 (d, 2H), 4.00 (m, 2H), 3.91 (m, 3H), 3.85 (t, 1H), 3.71 (m, 4H), 2.71 (m, 1H), 2.56 (m, 1H), 1.26 (t, 3H).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=34)=[N:8][CH:9]=2)[N:4]1[C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.[C:29]([CH2:31][C:32](ON1C(=O)CCC1=O)=[O:33])#[N:30]>CN(C=O)C>[C:29]([CH2:31][C:32]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:23]([N:4]2[C:3](=[O:2])[NH:11][C:10]3[C:5]2=[N:6][C:7]([C:12]2[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=24)=[N:8][CH:9]=3)[CH2:24]1)=[O:33])#[N:30]
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n([C@H]5CCCNC5)c4n3)c2c1
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC[C@H](n2c(=O)[nH]c3cnc(-c4cnn5ccc(C#N)cc45)nc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
To a solution of the compound obtained in example 6 (45 mg, 0.095 mmol) in anhydrous DMF (3 mL), 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (69 mg, 0.38 mmol) and anhydrous TEA (0.09 mL, 0.665 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO3 aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg2SO4, filtered and concentrated. The crude residue was flash chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 11.7 mg of the desired compound (29% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:23])=[C:12]3[CH:18]=[C:17]([C:19]#[C:20][CH2:21][OH:22])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([OH:36])=[O:35]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[CH:18]=[C:17]([C:19]#[C:20][CH2:21][OH:22])[S:16][C:13]=3[N:14]([CH2:33][C:34]([OH:36])=[O:35])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(C#CCO)cc2c1O
Reactant: O=C(O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
To a solution of N-(4-chlorobenzyl)4-hydroxy-2-(3-hydroxy-1-propynyl)-thieno[2,3-b]pyridine-5-carboxamide (Example No. 5) (0.250 g) in DMF (3 mL) is added K2CO3 (0.278 g) and bromoacetic acid (0.279 g). The reaction is heated to 100° C. and stirred for 18 h. An additional 0.200 g of bromoacetic acid is added and the reaction is stirred for an additional 18 h. The reaction mixture is concentrated in vacuo, and the resulting residue is dissolved in 10% NaOH and washed with CH2Cl2. The aqueous layer is acidified with conc. HCl and the resulting precipitate is filtered. This material is recrystallized 3 times from methanol to yield 0.068 g (24%) of the title compound as a tan solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:41]([OH:43])=O)=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C.[F:57][C:58]1[CH:63]=[CH:62][C:61]([C@H:64]([NH2:66])[CH3:65])=[CH:60][CH:59]=1>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([C:41]([NH:66][C@@H:64]([C:61]2[CH:62]=[CH:63][C:58]([F:57])=[CH:59][CH:60]=2)[CH3:65])=[O:43])=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)O)n3)cc12
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)N[C@H](C)c4ccc(F)cc4)n3)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinic acid (110 mg, 0.18 mmol) was suspended in THF (2 ml), cooled to 0° C., then 4-methylmorpholine (55.3 mg, 0.55 mmol) and ethylchloroformate (27.7 mg, 0.26 mmol) were added. The resulting mixture was stirred at 0° C. for 1 h, then (R)-1-(4-fluorophenyl)ethylamine was added. The reaction was warmed to RT and stirred for 1 h, then concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-5% MeOH/DCM) to provide (R)-3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-N-(1-(4-fluorophenyl)ethyl)picolinamide (100 mg, yield: 76%). MS (M+H)+: 724.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=O)=[CH:13][CH:12]=2)=[CH:7][C:6]=1Cl)=[O:4].[ClH:36].[NH2:37][OH:38].C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19](=[N:37][OH:38])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:13][CH:12]=2)=[CH:9][C:10]=1[Cl:36])=[O:4]
Reactant: NO
Reactant: COC(=O)c1ccc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)cc1Cl
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(-c2ccc(C(CC(=NO)c3ccnc(C)c3)c3ccccc3C)cc2)cc1Cl

Procedure:
In analogy to example 74, step 7, from 3-chloro-4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid methyl ester and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (4.2:1) as a colorless oil, MS (ESI+): m/z=499.3 ([M+H]+, 1Cl).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=O.[OH-].[Na+]>CO>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:1][C:2]([C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)=[O:3])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COc1ccc(C=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C=CC(=O)c2ccc(O)cc2)cc1OC

Procedure:
4-Hydroxy acetophenone, 1 (13.6 g, 100 mmol), 3,4-dimethoxy benzaldehyde, 5 (16.6 g, 100 mmol) and 50% aqueous sodium hydroxide (80 mL) in methanol (200 mL) were reacted under reflux as in 7 to yield 10. Yield 19.6 g (69%); mp 193-195° C.; MS (FAB) 285 (M++1); IR (KBr) 3443, 1643; 1H NMR (200 MHz, CDCl3) δ 10.45 (s, 1H), 8.10 (d, J=8.5 Hz, 2H), 7.81 (d, J=15.5 Hz, 1H), 7.66 (d, J=15.5 Hz, 1H), 7.52 (s, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.5 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][CH:14]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][C:16](OC)=[O:17].C(O)(=O)C>C1COCC1.O>[CH3:13][C@@H:14]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][C:16](=[O:17])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCC(C)CC(=O)OC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@H](C)CC(=O)CP(=O)(OC)OC
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of dimethyl methylphosphonate (32.5 g, 0.262 mol) in anhydrous THF (480 ml) was dropwise added 1.63N n-butyl lithium (160 ml, 0.261 mol) at -78° C. After stirring for 30 minutes, a solution of methyl l-3-methylheptanoate (16.5 g, 0.104 mol) in anhydrous THF (25 ml) was added dropwise, and the mixture was stirred at -78° C. for one hour and at room temperature for 2 hours. Acetic acid (19 ml) and water (100 ml) were added to the reaction mixture. After distilling off THF, the residue was extracted with ether (500 ml×3). The combined organic layers were washed with brine (250 ml×2), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give dimethyl (4S)-4-methyl-2-oxo-octylphosphonate (23.6 g, 0.094 mol, 90%, b.p.=124°-125° C./0.5 mmHg). The structure was confirmed by the following data.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH:13]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH:13]=[CH2:1]
Reactant: [Li]CCCC
Reactant: O=Cc1cnccc1Cl
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cnccc1Cl
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium bromide (4.45 g, 12.5 mmol) was suspended in THF (25 mL) under dry nitrogen and treated with butyllithium (2.5 M in hexanes, 5 mL). After stirring the suspension for 30 minutes, 4-chloropyridine-3-carboxaldehyde (1.47 g, 10.4 mmol) was added. After 2 hours at ambient temperature, the reaction was diluted with hexanes, filtered, and evaporated. The material thus obtained was used directly without further purification or characterization.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[C:10](=[O:11])[N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[S:7]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[O:11]=[C:10]1[N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:7][CH:6]1[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:32]
Reactant: CCOC(=O)CC1SC2(CCN(C(=O)OC(C)(C)C)CC2)N(CCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC1SC2(CCNCC2)N(CCc2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
In 56 ml of methylene chloride was dissolved 18.50 g of tert-butyl 2-(2-ethoxy-2-oxoethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decane-8-carboxylate. After adding 56 ml of trifluoroacetic acid at 0-5° C., the resulting mixture was stirred at the same temperature as above for 30 minutes and then at ambient temperature for 5 hours. The solvent was distilled off under reduced pressure, the residue was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 8.0 with saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Thus, 7.26 g of ethyl 2-(3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-2-yl)-acetate was obtained as a yellow oily product.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].CO.[CH3:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH:26]3[S:32][C:30](=[O:31])[NH:29][C:27]3=[O:28])=[CH:23][CH:24]=2)=[N:14][CH:15]=1.CCOCC>CCCCCCC>[CH3:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH:26]3[S:32][C:30](=[O:31])[NH:29][C:27]3=[O:28])=[CH:23][CH:24]=2)=[N:14][CH:15]=1.[S:1]([O-:5])([O-:4])(=[O:3])=[O:2]
Reactant: O=S(=O)(O)O
Agent: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Solvent: CCOCC
Solvent: CCCCCCC
Solvent: CO
Product: O=S(=O)([O-])[O-]

Procedure:
24 g of sulfuric acid was added slowly, at room temperature, to 250 ml of methanol followed by addition of 80 g of pioglitazone base with stirring. The mixture turned into a clear solution. 250 ml of ether was slowly added followed by 500 ml of heptane. A solid precipitated, and the suspension was stirred for 3 hours. The solid (98.4 g, yield was 96.5%) was collected by filtering and washed once with ether. The solid had a mp: 1113.5˜116.5° C. (recrystallized from methanol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[NH:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1.N#N>C(Cl)Cl>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: C1=CCNC1
Agent: N#N
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1N1CC=CC1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A mixture of 1-chloro-2-methoxy-4-nitrobenzene (2.71 g, 14.47 mmol) and 2,5-dihydro-1H-pyrrole (2.0 g, 28.9 mmol) was stirred at 100° C. under a stream of N2 for 10 h. The reaction was cooled to RT to give a brown solid which was dissolved in CH2Cl2 (200 mL), washed with 100 mL of 1 N NaOH solution and brine, dried over MgSO4, and concentrated. The resulting brown oil was purified by flash chromatography (silica gel, Hexanes:EtOAc, 100:0 to 80:20) to afford the title compound (2.67 g, 84% yield) as a orange solid: 1H NMR (500 MHz, CDCl3) δ 7.84 (dd, J=8.80, 2.50 Hz, 1H), 7.65 (d, J=2.50 Hz, 1H), 6.39 (d, J=8.80 Hz, 1H), 5.89 (s, 2H), 4.46 (s, 4H), 3.83 (s, 3H). HPLC retention time: 3.315 min; LCMS (ES): m/z 221 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:15](OC)(=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18].C[O-].[Na+]>CO>[CH2:11]([NH:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:1]2[C:15]([OH:21])=[C:16]([C:17]([O:19][CH3:20])=[O:18])[N:3]=[N:2]2)=[CH:14][CH:13]=1)=[O:9])[CH3:12]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)OC)c2O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.1 %

Procedure:
To a solution of 4-azido-N-ethylbenzamide (3.8 g, 20 mmol) obtained in Example 43a) in methanol (200 ml) was added dimethyl malonate (3.96 g, 30 mmol) at 0-5° C., and then 28% sodium methoxide in methanol solution (5.79 g, 30 mmol) was added. The mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated, and the residue was dissolved in water (50 ml) and adjusted to pH 2-3 with 1N hydrochloric acid. The precipitated crystals were filtered off, and the filtrate was neutralized with 6% aqueous sodium hydrogen carbonate solution. The mixture was concentrated to dryness, methanol (100 ml) was added to the residue, and the insoluble material was filtered off. The filtrate was concentrated to dryness. Ethanol (50 ml) was added to the residue and the precipitated crystals were collected by filtration, and dried to give the title compound as a white powder (2.5 g, 43%).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[ClH:11]>C(OCC)C>[Cl-:11].[OH:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[NH+:2]([CH3:10])[CH3:1]
Reactant: CN(C)c1cccc(O)c1
Reactant: Cl
Solvent: CCOCC
Product: C[NH+](C)c1cccc(O)c1
Product: [Cl-]

Procedure:
3-dimethylaminophenol, 10.2 g, was slurried in 75 mL of anhydrous diethyl ether and 82 mL of a 1 M HCl solution in ether was added by canula under positive nitrogen pressure. After two hours the white solid precipitate was collected on a fritted funnel, washed with ether and dried in vacuo.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].Br[CH2:11][C:12](=O)[C:13]([O:15]CC)=[O:14].C(=O)(O)[O-].[Na+]>O.C(#N)C>[CH3:4][C:3]1([CH3:5])[CH:2]([C:7]([OH:9])=[O:8])[NH:1][C:12]([C:13]([OH:15])=[O:14])=[CH:11][S:6]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(S)[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1(C)SC=C(C(=O)O)NC1C(=O)O
Yield: 34.5 %

Procedure:
To a solution of L-penicillamine (298 mg, 2.0 mmol) in water (5 mL) and acetonitrile (5 mL) was added ethyl 3-bromopyruvate (0.25 mL, 390 mg, 2.0 mmol) slowly. To the resulted mixture was added sodium bicarbonate aqueous solution till the pH about 5. Acetonitrile was removed under vacuum and some more water was added. The solution was extracted with methylene chloride. The water phase was separated and freeze-dried under high vacuum. The residue was chromatographed (silica gel, methylene chloride-methanol-acetic acid 100:5:0.3 to 100:10:0.3) to give 150 mg of product (yield 31%). 1HNMR (300 Hz, D3COD) δ (ppm) 6.17 (s, 1H), 4.23 (q, J=7.1 Hz, 2H), 3.79 (s, 1H), 1.48 (s, 3H), 1.31 (t, J=7.1 Hz, 3H), 1.29 (s, 3H). 13CNMR (75 Hz, D3COD) δ (ppm) 173.8, 164.0, 128.0, 102.4, 64.1, 62.2, 41.2, 28.3, 25.2, 14.7 ppm. MS (ESI) m/z 268 (M+Na, 100), 246 (M+1, 5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:12]([N:6]([CH2:5][CH2:4][CH2:3][CH2:9][CH2:8][CH3:7])[C:5]1[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COc1cc(N)cc(OC)c1
Reactant: CCCCCCBr
Product: CCCCCCN(CCCCCC)c1cc(OC)cc(OC)c1

Procedure:
3,5-dimethoxyaniline was bromided with n-hexylbromide so as to obtain 1-di-n-hexylamino-3,5-dimethoxybenzene. This was nitrosoized so as to obtain 1-di-n-hexylamino-3,5-dimethoxy-4-nitrobenzene.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:3]=1[C:4]([N:6]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:7][C:8]([CH3:10])=[CH2:9])=[O:5].C(O[Na])=O.CC([O-])=O.[Na+]>CN(C=O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:6]2[CH2:7][C:8]([CH3:10])([CH3:9])[C:2]3[C:3](=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)[C:4]2=[O:5])=[CH:13][CH:14]=1
Reactant: C=C(C)CN(Cc1ccc(OC)cc1)C(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: CC(=O)[O-]
Agent: O=CO[Na]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-(4-methoxy-benzyl)-N-(2-methyl-allyl)-5-nitro-benzamide (23.4 mmol) was dissolved in DMF (150 ml) and Et4NCI (4.25 g), HCO2Na (1.75 g) and NaOAc (4.99 g) were added. N2 was bubbled through the solution for 10 min, then Pd(OAc)2 (490 mg) was added and the mixture was stirred overnight at 70° C. The mixture was extracted with EtOAc, washed with sat'd NH4Cl, dried over MgSO4, filtered and concentrated until the compound precipitated as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(F)cc1C(=O)O
Product: CC(=O)Nc1ccc(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a flask containing acetic anhydride (60 mL) was slowly added 2-amino-5-fluorobenzoic acid (7.68 g, 0.05 mol) over 20 minutes and continued to stir over 2 hours at room temperature. The product was collected by filtration and allowed to dry to give 2-acetamido-5-fluorobenzoic acid (8.03 g, 82) as an off white solid.: m.p. 168°-170°; 1H NMR (400 MHz, DMSO-d6) δ 2.11 (s, 3H), 7.46 (dt, 1H), 7.65 (dd, 1H), 8.41 (dd, 1H), 10.83 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 25.3, 117.1, 117.4, 119.3, 121.2, 121.4, 122.9, 137.6, 156.0, 158.4, 168.7, 168.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+]>O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:16]/[N+:13]([O-:15])=[O:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(/C=C/[N+](=O)[O-])cc(OC)c1
Temperature: 0 °C

Procedure:
A solution of 3,5-dimethoxybenzaldehyde (34.5 g., 0.208 mole) and nitromethane (12.69 g., 0.208 mole) in 40 ml. of MeOH was cooled to 0° under N2 . A solution was prepared by dissolving NaOH (8.43 g., 0.211 mole) in 10 ml. of H2O then diluting to 20 ml. with ice-water. This solution was then added dropwise to the methanol mixture. After 15 minutes the reaction was diluted with ice-H2O and added slowly to a solution of 40 ml. concentrated HC1in 60 ml. H2O. The resulting precipitate (44 g.) was filtered and recrystallized from methanol to give 28.6 g. of product, m.p. 132°; reported, J. Org. Chem. 27, p. 376 (1962), m.p. 133.5-134.5.