Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:18]([F:19])=[CH:17][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#N)=[CH:10][C:9]=2[F:16])=[C:5]([O:20][CH3:21])[CH:4]=1)[CH3:2].[OH-:22].[Na+].Cl.C[OH:26]>C(OCC)(=O)C.O>[CH2:1]([C:3]1[C:18]([F:19])=[CH:17][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]([OH:26])=[O:22])=[CH:10][C:9]=2[F:16])=[C:5]([O:20][CH3:21])[CH:4]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCc1cc(OC)c(Oc2ccc(C#N)cc2F)cc1F
Reactant: CO
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc(OC)c(Oc2ccc(C(=O)O)cc2F)cc1F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzonitrile (420 mg, 1.45 mmol; which may be prepared as described in D1) in methanol (15 mL) was added an aqueous solution of 6N NaOH (7.3 mL, 43.6 mmol). The reaction mixture was heated to reflux (70° C.) and stirred overnight. After cooling with an ice bath, concentrated HCl (3.7 mL) was added slowly. The mixture was diluted with ethyl acetate and water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtrated and concentrated in vacuo to give the title product as a beige solid (447 mg, quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26].CCN(CC)CC>C1COCC1>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: O=C=Nc1ccccc1Br
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Br
Reaction time: 3 h
Yield: 113.5 %

Procedure:
to a stirred mixture of tert-butyl 4-amino-3-methylphenylacetate (780 mg, 3.30 mmol), 2-bromo phenyl isocyanate (0.41 ml, 3.30 mmol) in THF (7 ml) was added Et3N (0.092 ml, 0.66 mmol) at room temperature. After 3 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2bromophenyl)ureido]-3-methylphenylacetate (1.57 g, 93%) as a pale yellow powder. mp 138-145° C. (dec.); 1H-NMR (CDCl3) δ1.44 (s, 9H), 2.33 (s, 3H), 3.51 (s, 2H), 6.90 (dt, J=9.0, 1.4 Hz, 1H), 7.18-7.31 (m, 4H), 7.39 (dd, J=8.1, 2.9 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 8.22 (d, J=8.3 Hz, 2H); Anal. Calcd. for C20H22BrN2O3.0.2H2O: C, 56.80; H, 5.58; N, 6.62. Found: C, 56.85; H, 5.42; N, 6.62.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([C:13](OC)=[O:14])[C@@H:11]([C:17](O)=[O:18])[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>O1CCCC1>[CH2:20]([N:10]1[C@H:11]2[CH2:17][O:18][C:13](=[O:14])[C@H:12]2[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@H]1[C@@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
A solution of (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (mp., 149°-150° C., [α]36525 =-27.6° at c=1 in DMF, 368 mg) in tetrahydrofuran (6 ml) was added dropwise to a mixture of sodium borohydride (98 mg) and tetrahydrofuran (6 ml) at 5°-10° C. The obtained mixture was allowed to warm up to room temperature and to react at the same temperature for 20 hours. Then, 1N hydrochloric acid (10 ml) was added to the reaction mixture. The mixture was stirred at 55°-60° C. for 30 minutes and concentrated under reduced pressure. The residue was extracted with chloroform (30 ml) and water (30 ml). The chloroform layer was washed successively with 5% aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel column to yield ( 3aS,6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione (45 mg). M.P., 116°-117° C. [α]D25 =+60.9° (c=1, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=1.[Sn](Cl)(Cl)(Cl)Cl.ClCCCl.[N+](=[CH:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[N-]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc[nH]c3=O)c(Cl)cc2F)c1=O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h

Procedure:
Into a mixture of 1.0 g of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-1H-pyridin-2-one, 121 mg of tin tetrachloride and 40 ml of 1,2-dichloroethane, 0.4 ml of ethyl diazoacetate (purity: 90%) is dropped at room temperature over 2 hours. After dropping, the reaction mixture is further stirred for 2 hours, and subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=2/1) to give 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-2-(ethoxycarbonylmethoxy)pyridine.
Reaction SMILES: Cl[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:3][C:4]#[N:5].[Se-2:12].[Na+].[Na+].Cl[CH2:16][C:17]#[N:18]>>[NH2:5][C:4]1[CH:3]=[C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[Se:12][C:16]=1[C:17]#[N:18]
Reactant: [Se-2]
Reactant: N#CC=C(Cl)c1ccccc1
Reactant: N#CCCl
Agent: [Na+]
Product: N#Cc1[se]c(-c2ccccc2)cc1N
Yield: 53 %

Procedure:
The reaction of 3-chloro-3-phenylprop-2-enenitrile, sodium selenide and chloroacetonitrile as described earlier gave the product as a brown color solid (4.8 g, 53%), mp 162-164° C. (decomp). 1H NMR (400 MHz, CDCl3): δ 7.46-7.49 (2H, m), 7.37-7.39 (3H, m), 7.01 (1H, s), 4.55 (2H, br s).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[N:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][CH3:19])=[CH:13][CH:12]=1>CCOC(C)=O.O>[N:11]1[CH:16]=[CH:15][C:14]([C:17](=[N:2][OH:3])[CH2:18][CH3:19])=[CH:13][CH:12]=1
Reactant: CCC(=O)c1ccncc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCC(=NO)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Hydroxylamine hydrochloride (2.8 g, 40.7 mmol) and sodium acetate (3.3 g, 40.7 mmol) were added to 20 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. 1-(Pyridin-4-yl)propan-1-one (5.0 g, 37.0 mmol) was added and the mixture was stirred at room temperature for 20 hours. Water (50 mL) and EtOAc (50 mL) were added and the organic layer was separated. The aqueous layer was basified with solid sodium bicarbonate and extracted with additional EtOAc. The combined organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 5.3 g of the title compound. MS: (+) m/z 151.36 (M+1).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[Na].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.CN(C)C=O>CCOCC.O>[O:3]=[S:1]1(=[O:2])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:5](=[O:6])[N:4]1[CH2:18][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: BrCCCCBr
Agent: [Na]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Temperature: 50 °C

Procedure:
The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 21, 583-4 was modified: A mixture of 6 g of sodium saccharin, 100 mL of 1,4-dibromobutane, and 5 mL of N,N-dimethylformamide was heated at 50° C. overnight. After cooling to ambient temperature, the mixture was diluted with 250 mL of ether and 50 mL of water. The aqueous layer was extracted with two additional 50 mL portions of ether and the combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The excess 1,4-dibromobutane was removed by short path vacuum distillation and the oily residue purified by crystallization from ether-hexane, mp 71-2° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.[CH:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C([O-])([O-])=O.[Na+].[Na+]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:35]5[CH:36]=[CH:37][C:32]([CH:30]=[O:31])=[CH:33][CH:34]=5)[CH:3]=4)[N:8]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=4)(=[O:21])=[O:22])[CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(C=O)cc4)cnc32)cc1
Temperature: 150 °C

Procedure:
To a solution of 5-bromo-3-(1H-indol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine [Intermediate B] (0.20 g, 0.43 mmole) in CH3CN (4 mL) in a Personal Chemistry microwave reaction vial was added 4-formylphenylboronic acid (64 mg, 0.43 mmol), bis(triphenylphosphine)-palladium(II) dichloride (40 mg, 0.057 mmol), and 1 M Na2CO3 (2 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 10 min in a Personal Chemistry Optimizer. The organic layer was separated, filtered, and partitioned between EtOAc and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give Intermediate AJ. HPLC retention time: 3.01 minutes. MS ESI (m/z): 492.4 (M+H)+, calc. 491.
Reaction SMILES: [CH2:1]([CH:4]([S:8]([CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])(=[O:10])=[O:9])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[C:17](NC(=O)CCC(N)=O)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].CN1CCOCC1>C(Cl)Cl>[CH2:20]([O:19][C:17]([NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][S:8]([CH:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])(=[O:9])=[O:10])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)CCC(=O)NC(=O)OCc1ccccc1
Reactant: CCCC(CCC)S(=O)(=O)C[C@H](N)C(=O)O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCC(CCC)S(=O)(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 4 h

Procedure:
3-[(1-Propylbutyl)sulfonyl]alanine (LXXXIII, 7.8 g, 27 mmole) and N-CBZ succinamide (7.4 g, 30 mmole) are mixed in methylene chloride (100 ml). The reaction is cooled to 0°, and NMM (6.9 g) is added dropwise. The reaction is allowed to warm to 20–25° and stirred for 4 hours at which point HPLC analysis indicated complete reaction. The reaction mixtue is concentrated under reduced pressure and partitioned between ethyl acetate and hydrochloric acid (1 N). The organic phase is washed with water, saline, dried over sodium sulfate, and concentrated under reduced pressure to give N-[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]alanine (LXXXIV) that is used without further purification, M+H=386.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[C:10](=[N:18][OH:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11].[H-].[Na+].O>CN(C=O)C.C(Cl)Cl>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:19][N:18]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[N:3]=1
Reactant: CC(=NO)c1ccccc1
Reactant: Nc1nc(Cl)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NOc1ncc(F)c(N)n1)c1ccccc1
Temperature: 100 °C
Yield: 34 %

Procedure:
To a magnetically stirred mixture of 4-amino-2-chloro-5-fluoropyrimidine (0.10 g, 0.68 mmol) and acetophenone oxime (0.092 g, 0.68 mmol) in dry DMF (3 mL) in a 5 mL Biotage Iniator microwave vessel was added NaH (0.027 g of a 60 wt. % suspension, 0.68 mmol) under a N2 atmosphere. After gas evolution ceased, the resulting mixture was sealed with a Biotage Initiator microwave septa cap and heated to 100° C. in a Biotage Initiator microwave for 60 min. The contents were poured into a vial with water (5 mL) and CH2Cl2 (5 mL), and neutralized with a few drops of 2NHCl. The phases were separated and the organic extract was dried over MgSO4, filtered, and evaporated under a stream of nitrogen. The crude contents were purified on silica (EtOAc/hexanes gradient) and evaporation of the product fractions gave 0.057 g (34%) of 1-Phenyl-ethanone-O-(4-amino-5-fluoro-pyrimidin-2-yl)oxime as an off-white solid: mp 163-165° C.; 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=2.6 Hz, 1H), 7.75 (m, 2H), 7.42 (m, 3H), 5.25 (bs, 2H), 2.51 (s, 3H); HPLC-MS (ESI) m/z 247 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.[H-].[Na+].[CH3:12][Si:13]([CH2:16][CH2:17][O:18][CH2:19]Cl)([CH3:15])[CH3:14]>>[F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][N:6]([CH2:19][O:18][CH2:17][CH2:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: FC(F)(F)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cnc(C(F)(F)F)c1

Procedure:
Reaction of 4-trifluoromethyl-1H-imidazole (301 mg, 2.21 mmol), 95% NaH (61 mg, 2.4 mmol), and SEMCl (406 mg, 2.44 mmol) gave the title compound as a brown oil that was used without further purification. 1H NMR (CDCl3) □0.00 (s, 9H), 0.93 (m, 2H), 3.51 (m, 2H), 5.30 (s, 2H), 7.39 (s, 1H), 7.64 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]=4[CH:6]2[CH2:5][CH:4]([C:18]([OH:20])=[O:19])[CH2:3]1)[NH:11][CH:10]=3.[OH-].[K+].CN(C=O)C.[C:28]1(C)[CH:33]=[CH:32]C(S(OC(CC)CC)(=O)=O)=[CH:30][CH:29]=1>O>[CH2:29]([CH:28]([N:11]1[C:12]2[C:17]3[C:9]([CH2:8][C@@H:7]4[C@@H:6]([C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:5][CH:4]([C:18]([OH:20])=[O:19])[CH2:3][N:2]4[CH3:1])=[CH:10]1)[CH2:33][CH3:32])[CH3:30]
Reactant: CCC(CC)OS(=O)(=O)c1ccc(C)cc1
Reactant: CN1CC(C(=O)O)CC2c3cccc4[nH]cc(c34)CC21
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)n1cc2c3c(cccc31)[C@H]1CC(C(=O)O)CN(C)[C@@H]1C2
Yield: 59.8 %

Procedure:
A 250 ml, three-neck round bottom flask was charged with 10.0 g (33.9 mmol) of 92% pure 9,10-dihydrolysergic acid, 10.3 g (158 mmol) of 86% pure powdered potassium hydroxide and 75 ml of DMF. The mixture was stirred until the solid constituents were completely dissolved, and 17.9 g (73.9 mmol) of p-toluenesulfonic acid, 1-ethylpropyl ester was added. The reaction mixture was stirred at room temperature overnight and 300 ml of deionized water was added. The mixture was filtered, and 1N hydrochloric acid was added to the filtrate until the pH was adjusted to approximately 6.5. The precipitated solid was collected by vacuum filtration and rinsed with water to provide 6.9 g of 1-(1-ethylpropyl)-6-methylergoline-8-carboxylic acid. The identity of the solid was determined by thin layer chromatography employing chloroform:methanol:acetic acid (18:6:1, v:v:v) as the solvent system as compared to an authentic reference standard. The products obtained from Example 1 and Example 2 were combined to provide 7.6 g of solid, which was recrystallized from methanol to provide 2.1 g of the desired product following drying of the solid in vacuo. The purity of the product was 95.6% as determined by HPLC as compared to an authentic reference standard.
Reaction SMILES: ClC1C(=O)C2C(C(=[O:13])C=1Cl)=CC=CC=2.N([O-])=O.[Na+].[N+:19]([C:22]1[C:23](=[O:33])[C:24]2[C:29]([C:30](=[O:32])[CH:31]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)([O-:21])=[O:20]>CO.O>[OH:13][C:31]1[C:30](=[O:32])[C:29]2[C:24]([C:23](=[O:33])[C:22]=1[N+:19]([O-:21])=[O:20])=[CH:25][CH:26]=[CH:27][CH:28]=2
Reactant: O=C1C=C([N+](=O)[O-])C(=O)c2ccccc21
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1C(O)=C([N+](=O)[O-])C(=O)c2ccccc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A suspension of 2,3 -dichloro-1,4-naphthoquinone (6.83g; 0.03 mole) in methanol (40 ml) was stirred during the addition of a solution of sodium nitrite (6.9g; 0.1 mole) in water (50ml) and the mixture stirred at 80° C for 3 hours. Solution was attained after about 1 hr and the nitro naphthoquinone began to separate after 2 hrs. After cooling in ice and the yellow crystalline solid was filtered off, taken up in water (200ml), charcoalized and precipitated the product by addition of one-third the volume of concentrated hydrochloric acid, filtered off, washed well with 5N HCl and dried in vacuo over P2O5 /NaOH to give 5.30 g (81%) of material of m.p. 162°-163° C (d) which was identical to that prepared above.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[Cl-].[Li+]>CN(C)C=O.C(OCC)(=O)C>[OH:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: COc1cc([N+](=O)[O-])ccc1C#N
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc([N+](=O)[O-])cc1O
Temperature: 160 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
To a solution of 2-methoxy-4-nitrobenzonitrile (5.0 g, 28.1 mmol) in N,N-dimethylformamide (28 mL) was added lithium chloride (2.38 g, 56.2 mmol), and the mixture was stirred at 160° C. for 16 hr. The reaction solution was cooled to room temperature, diluted with ethyl acetate (300 mL), washed with 1% aqueous citric acid solution (150 mL), water (150 mL) and saturated brine (150 mL×2), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→30/70), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate to give the title compound (3.98 g, 86%) as a yellow-brown solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16]C(C)([O-])C.[K+].CI>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-Benzyl-3-methyl-piperidin-4-one (2.03 g, 10 mmol) in THF (10 mL) was added potassium t-Butoxide (1.1 g, 10 mmol) and methyl iodide (0.62 mL, 10 mmol). The solution was then stirred at room temperature for about 72 hours. The reaction was quenched with brine and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo, then purified by flash chromatography on silica gel (35 g SiO2, gradient elution from 100% hexane to 100% ethyl acetate) to yield the title compound as a colorless oil.
Reaction SMILES: [NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([O:46]C)=O)[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].O.[NH2:59][NH2:60]>CO>[NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([NH:59][NH2:60])=[O:46])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: NN
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)NN
Reaction time: 20 h

Procedure:
3.97 g of Z-Asn-Lys(BOC)-Phe-His-OMe are dissolved in 20 ml of boiling methanol. 2.5 ml of hydrazine hydrate are added to the solution whilst it is still at about 30° C. and the mixture is allowed to stand for 20 hours at room temperature. The peptide-hydrazide is precipitated by adding water, filtered off and washed with water until free of hydrazine. The product is reprecipitated from dimethylformamide-water.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][CH:13]([CH3:41])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][C:23]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=4)=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:38][CH2:39][CH3:40].[OH-].[NH4+:43]>C(Cl)(Cl)Cl.ClCCl>[CH3:12][CH:13]([CH3:41])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][C:23]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=4)=[CH:22][C:21]=3[N:20]=[C:19]([NH2:43])[C:18]=2[N:17]=[C:16]1[CH2:38][CH2:39][CH3:40]
Reactant: CCCc1nc2cnc3cc(Oc4ccc([N+](=O)[O-])cc4)ccc3c2n1CC(C)C
Reactant: [NH4+]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(Oc4ccc([N+](=O)[O-])cc4)ccc3c2n1CC(C)C
Reaction time: 0.5 h

Procedure:
Part B of the general methods described for Examples 35-40 was followed using 2.00 g of 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol to provide 2.33 g of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinoline as a yellow solid. Parts C and D of the general methods described for Examples 35-40 were replaced by the following procedure. mCPBA (0.853 g, 2.97 mmol) was added in one portion to a solution of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinoline (1.00 g, 2.47 mmol) in chloroform (17 mL), and the reaction was stirred for 30 minutes. Ammonium hydroxide (17 mL) was then added, followed by/7-toluenesulfonyl chloride (0.710 g, 3.70 mmol). The reaction was stirred for 16 hours and then diluted with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic solutions were washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a brown solid. The solid was recrystallized from acetonitrile to provide 0.680 g of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a reddish-brown, crystalline solid, mp 209-211° C.