Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[C:16]2=[O:31])=[C:12]2[C:8]([C:9]([CH3:34])=[C:10]([CH3:33])[N:11]2[CH3:32])=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>O1CCOCC1.O>[CH3:1][O:2][C:3]([C:5]1[C:13]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:16]2=[O:31])=[C:12]2[C:8]([C:9]([CH3:34])=[C:10]([CH3:33])[N:11]2[CH3:32])=[CH:7][CH:6]=1)=[O:4]
Reactant: CCOC(=O)CCn1c(=O)n(Cc2c(C(=O)OC)ccc3c(C)c(C)n(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2c(C)c(C)n(C)c2c1Cn1c(=O)n(CCC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
To a solution of 7-[3-(2-Ethoxycarbonyl-ethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl]-1,2,3-trimethyl-1H-indole-6-carboxylic acid methyl ester (60 mg, 0.13 mmol) in 1,4-dioxane (5 mL) and H2O (2 mL) was added LiOH (6.4 mg). The solution was stirred at room temperature for 5 hours. The solution was concentrated and the residue was purified by CombiFlash with 10% MeOH in CH2Cl2 as the eluent to afford the desirable product 7-[3-(2-Carboxy-ethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl]-1,2,3-trimethyl-1H-indole-6-carboxylic acid methyl ester (10 mg, 17%) as a white solid. LC-MS (M+): 435.36.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:16]([CH:18]([NH2:21])[CH2:19][CH3:20])[CH3:17]>>[CH2:16]([CH:18]([NH:21][C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:19][CH3:20])[CH3:17]
Reactant: CCC(N)CC
Reactant: Cc1cnc2c(Cl)nc3ccccc3n12
Product: CCC(CC)Nc1nc2ccccc2n2c(C)cnc12

Procedure:
By reaction of 4-chloro-1-methylimidazo[1,2-a]quinoxaline (example 2) with 1-ethylpropylamine, according to a procedure that is similar to that followed in example 3 there is obtained 4-(1-ethylpropylamino)-1-methylimidazo[1,2-a] quinoxaline. m.p. (DSC)=75.9° C. (onset); IR (KBr): 3231, 2965, 1546 cm-1 ; 1H-NMR (CDCl3): δ8.0 (1H,dd), 7.7 (1H,dd), 7.4÷7.1 (3H,m), 5.9 (1H,d), 4.2 (1H,m), 2.85 (3H,s), 1.65 (4H,m), 0.95 (6H,t); UV (EtOH): λmax =221, 241, 268, 298, 313 nm. Elementary analysis for C14H20N4 (m.w. 268.36): calcd. C 71.61, H 7.51, N 20.83%; found C 71.12, H 7.53, N 20.79%.
Reaction SMILES: [N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([N:12]3[C:16]4=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]4[CH:14]=[N:13]3)[CH:9]=[CH:10][CH:11]=2)[NH:3][CH:2]=1.[H-].[Na+].[C:24](Cl)(=[O:26])[CH3:25]>CN(C=O)C>[NH2:21][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([C:8]3[CH:7]=[C:6]([C:4]4[N:3]=[CH:2][N:1]([C:24](=[O:26])[CH3:25])[CH:5]=4)[CH:11]=[CH:10][CH:9]=3)[N:13]=[CH:14][C:15]=12
Reactant: CC(=O)Cl
Reactant: Nc1ncnc2c1cnn2-c1cccc(-c2cnc[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1cnc(-c2cccc(-n3ncc4c(N)ncnc43)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0.6 %

Procedure:
Title compound 6A, 1-[3-(3H-Imidazol-4-yl)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (30 mg, 1.0 eq, 0.11 mmol) was dissolved in DMF (2 ml) and to this was added sodium hydride as a 60% dispersion in oil (5 mg, 1.1 eq, 0.12 mmol), the mixture was then stirred under an inert atmosphere for 20 minutes. To this was added acetyl chloride (7.7 μl, 1.1 eq, 0.12 mmol) the reaction was the stirred for 18 hours and allowed to warm to room temperature. Solvent was then remove in vacuo. The resultant residue was purified using mass-directed preparative HPLC to yield the compound as an off white solid (2.1 mg, 0.0007 mmol, 6%). LCMS: [M+H]+=320, Rt=1.32 min, 87% purity.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([C:7]1[CH2:11][CH2:10][O:9][CH:8]=1)=[O:6])[CH3:2].[CH2:13]([OH:15])[CH3:14].BrN1C(=O)CCC1=O>ClCCl>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH:7]1[CH2:11][CH2:10][O:9][CH:8]1[O:15][CH2:13][CH3:14])=[O:6])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)C(=O)C1=COCC1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)C(=O)C1CCOC1OCC
Temperature: 7.5 °C

Procedure:
Ethyl-2-(4,5-dihydrofuran-3-yl)-2-oxoacetate (100 g) was dissolved in dichloromethane (500 ml). Ethanol (150 ml) was added to reaction mass and then reaction mass was cooled to 5 to 10° C. N-bromosuccinimide (115 g) was added lot wise by maintaining temp below 10° C. Reaction mass was then stirred at 20-30° C. till completion of reaction. Reaction mass was washed with sodium bicarbonate solution (8%, 3×400 ml). Sodium sulphite solution (15%, 1700 ml) was charged to dichloromethane layer. Reaction mass was stirred for 8 hrs at 25-35° C. Organic and aqueous layer separated. Dichloromethane layer was washed with water (2×340 ml). Dichloromethane layer was then concentrated to residue to get Ethyl-2-(2-ethoxytetrahydrofuran-3-yl)-2-oxoacetate (Yield 114 g)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[C:33]([CH3:35])[N+:32]([O-:36])=[C:31]([CH3:37])[CH:30]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:34]=[C:33]([CH3:35])[N+:32]([O-:36])=[C:31]([CH3:37])[CH:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyridine-N-oxide in Step 4. LC-MS Method 2 tR=1.185, m/z=459.1; 1H NMR (CDCl3) 1.11 (s, 3H), 1.18 (s, 3H), 1.57 (d, 3H), 2.20 (s, 2H), 2.22-2.35 (m, 2H), 2.38-2.49 (m, 1H), 2.72 (s, 6H), 2.91 (m, 1H), 5.70 (m, 1H), 7.08 (d, 2H), 7.31 (m, 3H), 7.37 (m, 4H), 7.43 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:14]=[CH:15]/[CH2:16][C@@H:17]([C:26]([NH:28][C@H:29]([C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:27])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][CH2:16][C@@H:17]([C:26]([NH:28][C@H:29]([C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[C:30]([CH3:31])([CH3:32])[CH3:33])=[O:27])[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C/C=C/c1ccc(-c2ccccc2)c(Cl)c1)CC(=O)OC(C)(C)C)C(C)(C)C)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCc1ccc(-c2ccccc2)c(Cl)c1)CC(=O)OC(C)(C)C)C(C)(C)C)c1ccccc1
Yield: 74.5 %

Procedure:
A mixture of tert-butyl (3R,5E)-6-[3-chloro-(4-phenyl)phenyl]-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)hex-5-enoate (936 mg, 1.52 mmol) and p-toluenesulphonyl hydrazide (1.41 gm, 7.60 mmol) in toluene (15 mL) was stirred under nitrogen at reflux for 4 h. After being cooled, the mixture was diluted with ether (150 mL), and washed with water (50 mL), 0.5M hydrochloric acid (50 mL) and saturated aqueous sodium chloride (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane/ethyl acetate) to give tert-butyl (3R)-6-[3-chloro-(4-phenyl)phenyl]-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino)carbonyl)hexanoate (701 mg, 74%), as a colourless foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[O:26][C:27]1[O:31][CH:30]=[C:29]([C:32](Cl)=[O:33])[CH:28]=1>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[O:26][C:27]1[O:31][CH:30]=[C:29]([C:32]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH:11]=3)[CH2:6][CH2:5]2)=[O:33])[CH:28]=1
Reactant: O=C(Cl)c1coc(Oc2cc(Cl)cc(Cl)c2)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCNC(=O)c3coc(Oc4cc(Cl)cc(Cl)c4)c3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(2-aminoethyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-(3,5-dichlorophenoxy)-3-furoyl chloride: ESMS m/e: 544.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH3:11].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[F:12])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH3:11]
Reactant: CCOc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2ccccc2F)c(Cl)c1Cl
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A mixture of 2,3-dichlorophenetole (57.3 g., 0.3 mole), 2-fluorobenzoyl chloride (47.8 g., 0.3 mole) and methylene chloride (300 ml.) at 5° C. was stirred vigorously and treated with finely powdered aluminum chloride (42.6 g., 0.32 ml.). The reaction mixture was slowly warmed to room temperature and then stirred overnight. The reaction mixture was decomposed with ice/concentrated hydrochloric acid (50 ml.) and the aqueous solution was extracted twice with methylene chloride. The combined organic extracts were washed with aqueous sodium bicarbonate solution and finally with aqueous sodium chloride solution. The methylene chloride solution was dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue on triturating with methanol gave the product 55 g., m.p. 94°-95° C. This material was used in the next step without additional purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][O:9][CH2:10][CH3:11])[CH3:2].C[Al](C)C.[Cl:16][C:17]1[CH:37]=[CH:36][C:20]2[C:21](=[O:35])[C:22]3[C:29]([C:30](OCC)=[O:31])=[N:28][NH:27][C:23]=3[C:24](=[O:26])[NH:25][C:19]=2[CH:18]=1>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:37]=[CH:36][C:20]2[C:21](=[O:35])[C:22]3[C:29]([C:30](=[O:31])[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:7][CH2:8][O:9][CH2:10][CH3:11])=[N:28][NH:27][C:23]=3[C:24](=[O:26])[NH:25][C:19]=2[CH:18]=1
Reactant: CCOCCNCCOCC
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCOCCN(CCOCC)C(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reaction time: 0.33 h
Yield: 44.7 %

Procedure:
Bis-(2-ethoxyethyl)amine (560 μL, 3.13 mmol) was added to a solution of trimethylaluminum in toluene (1.56 mL, 3.13 mmol) and the solution was stirred for 20 minutes. A portion (424 μL) of the resulting solution was added to a solution of 7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (100 mg, 0.313 mmol) in toluene (780 μL). The resulting solution was stirred for 4.5 hours at room temperature and then quenched with aqueous hydrochloric acid (1.5 mL, 1N) and water (20 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL) and the organic layers were concentrated on a rotary evaporator. The crude product was purified by flash chromatography eluting with chloroform:2-propanol (99:1-80:20) to give the title compound (60.8 mg, 45% yield, m.p. 202° C.).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[S:14][C:15]([S:18][CH3:19])=[N:16][N:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:20][C@@H:21]1[CH2:25][CH2:24][C@@:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[C:22]1([CH3:36])[CH3:35])(=[O:3])[NH2:2].[OH:37]OS([O-])=O.[K+]>CC(C)=O.O>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[S:14][C:15]([S:18]([CH3:19])=[O:37])=[N:16][N:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:20][C@@H:21]1[CH2:25][CH2:24][C@@:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[C:22]1([CH3:36])[CH3:35])(=[O:3])[NH2:2]
Reactant: O=S([O-])OO
Reactant: CSc1nnc(-c2cc3c(N[C@@H]4CC[C@](C)(NC(=O)OC(C)(C)C)C4(C)C)c(C(N)=O)cnn3c2)s1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)c1nnc(-c2cc3c(N[C@@H]4CC[C@](C)(NC(=O)OC(C)(C)C)C4(C)C)c(C(N)=O)cnn3c2)s1
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
A solution of tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(5-(methylthio)-1,3,4-thiadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (306.2 mg, 0.576 mmol) and oxone (531 mg, 0.864 mmol) in acetone (3 mL) and water (3 mL) was stirred at RT for 4 hrs. The reaction mixture was diluted with 30 mL of water which was stirred for 30 minutes. The solid was collected to give the desired tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(5-(methylsulfinyl)-1,3,4-thiadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (264.5 mg, 77% yield). MS (ES+) m/z: 548.08 (M+H); HPLC retention time: 3.296 min (analytical HPLC Method F).
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[NH:14][C:13]1[C:8]3=[CH:9][CH:10]=[C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]2=1.[Br:22]Br.O>ClCCl>[Br:22][C:10]1[CH:9]=[C:8]2[C:13]([NH:14][C:15]3[C:7]2=[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=[CH:17][CH:16]=3)=[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=12
Reactant: c1ccc2c(c1)ccc1c2[nH]c2ccc3ccccc3c21
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Product: Brc1cc2c([nH]c3ccc4ccccc4c32)c2ccccc12
Yield: 160.8 %

Procedure:
10.3 g of 7H-dibenzo[a,g]carbazole was dissolved in dichloromethane (150 mL) at 0° C. with stirring. To this was dropped a dichloromethane solution of bromine (3.1 g in dichloromethane). After being stirred at room temperature for 2 h, the solution was poured into 200 mL of water, filtered, and washed with 500 mL water. The white residue was recrystallized in ethanol and yielded 12-bromo-7H-dibenzo[a,g]carbazole as colorless crystals (10.8 g).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:16]1([S:22][C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1ccccc1
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)cc1Sc1ccccc1
Yield: 85.2 %

Procedure:
A mixture of 2-nitro-4-trifluoromethylbenzonitrile (8.64 g), thiophenol (4.4 g), potassium carbonate (6.9 g) in acetonitrile was heated at reflux for 4 hours. After cooling, the mixture was poured into water and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was triturated with hexane to give 2-phenylsulphenyl-4-trifluoromethylbenzonitrile as a white solid (9.5 g), m.p. 51° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH3:22])=[CH:16][C:15]=3[N+:23]([O-])=O)=[C:11]([C:27]([OH:29])=[O:28])[N:10]=[N:9]2)=[CH:5][CH:4]=1.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:23][C:15]1[CH:16]=[C:17]([CH3:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:13]([C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=2)[N:9]=[N:10][C:11]=1[C:27]([OH:29])=[O:28])=[O:26]
Reactant: COc1ccc(Cn2nnc(C(=O)O)c2C(=O)c2cc(OC)c(C)cc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(Cn2nnc(C(=O)O)c2C(=O)c2cc(OC)c(C)cc2N)cc1
Yield: 92 %

Procedure:
Next, 1-(4-methoxybenzyl)-5-(5-methoxy-4-methyl-2-nitrobenzoyl )-1,2,3-triazole-4-carboxylic acid (c-2': MP) (252 mg, 0.591 mmole) was dissolved in a mixed solvent of ethanol (10 ml) and ethyl acetate (10 ml), and reduced in the presence of 10% palladium on carbon (31 mg) under the hydrogen atmosphere at room temperature overnight to give 5-(2-amino-5-methoxy-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylic acid (c-2: MP) (216 mg, 92%).
Reaction SMILES: Cl[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[OH-].[Na+]>CN(C=O)C>[N:18]1([C:2]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[O:17])=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]3)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Reactant: c1c[nH]cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=Cc1c2ccccc2c(-n2ccnc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 10-chloro-9-anthraldehyde (Aldrich, 15 g, 0.062 mol), imidazole (Aldrich, 10.2 g, 0.15 mmol) and DMF (300 mL) was warmed to 55° and treated with KotBu (MCB, 7.0 g, 0.07 mol) and stirred for 30 min. The reaction mixture was poured into 0.1N NaOH (1.5 L). The precipitate was filtered and then chromatographed on a plug of SiO2 (500 g) using CH2Cl2 (3 L) as the initial eluting solvent to remove starting material and byproducts. The yellow product band was then eluted with EtOAc (2 L) to yield, after removal of solvent and drying, 12.29 g (73%) of 10-(1H-imidazol-1-yl)-9-anthracenecarbaldehyde mp 194°-196°, (C, H, N), (EtOAc).
Reaction SMILES: [N-:1]([C:4]#[N:5])[C:2]#[N:3].[Na+].[NH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]>O.Cl>[NH2:3][C:2]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[N:1][C:4]#[N:5]
Reactant: COC(=O)c1cccc(N)c1
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cccc(NC(N)=NC#N)c1

Procedure:
To sodium dicyanamide in 5 mL of deionized water was added dropwise a solution of methyl 3-aminobenzoate (Aldrich, 1.30 g, 8.6 mmol) in 15 mL of 1N HCl. The resulting clear solution was heated at 80°-90° C. for 2 h. The precipitate was collected through filtration, crystallized from chloroform-methanol, dried in air followed by drying in a pistol at acetone reflux in vacuo to give 1.84 g (quantitative) of methyl 3-[amino(cyanoiminomethyl)]aminobenzoate as a white solid, mp 203°-204° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].[N:19]([O-:21])=[O:20].[Na+]>C(O)(C(F)(F)F)=O>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: O=N[O-]
Reactant: CNS(=O)(=O)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a solution of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at −10° C. was added NaNO2 (0.097 g, 1.14 mmol) in portions over 5 min. The resulting solution was stirred at −10° C. for 1 h, then was allowed to warm to room temp., and was concentrated under reduced pressure. The residue was separated between EtOAc (10 mL) and water (10 mL). The organic phase was sequentially washed with water (10 mL) and a saturated NaCl solution (10 mL), dried (MgSO4) and concentrated under reduced pressure to give 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.20 g). This material carried on to the next step without further purification.
Reaction SMILES: C[Si](C)(C)[C:3]1[O:7][C:6]([CH3:8])=[C:5]([CH2:9][O:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1C(I)=C([OH:39])C(I)=C2OC3C(C4(OC(=O)C5C(Cl)=C(Cl)C(Cl)=C(Cl)C4=5)C=12)=CC(I)=C(O)C=3I.O=O.C(=O)=O.CC(C)=O>C1COCC1>[C:11]([O:10][CH2:9][C:5]1[CH:6]([CH3:8])[O:7][C:3](=[O:39])[C:4]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C1OC2(c3cc(I)c(O)c(I)c3Oc3c2cc(I)c(O)c3I)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CCCCCCCCCCCC(=O)OCc1c(C)oc([Si](C)(C)C)c1-c1ccccc1
Agent: O=C=O
Agent: O=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)OCC1=C(c2ccccc2)C(=O)OC1C
Yield: 27 %

Procedure:
The solution of Compound 15 and Rose Bengal in THF was saturated with O2, then cooled to approximately -5° C. (dry ice/acetone bath) and irradiated with a 150 watt flood lamp (maintaining the temperature of the mixture at -5° to 0° C.) for 3 hours. The reaction mixture was then filtered and concentrated to a pink oil which was purified by column chromatography (eluent, EtOAc/hexanes, 1:20 to 1:4) to give 3.4 g (27%) of pure title compound as a colorless oil. An additional 3 g (approximately 25%) of a mixture of the title compound and the 5-desmethyl derivative (ratio 1:1 by proton NMR integration) was also obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.S(O)(O)(=O)=O.C[NH:18][C:19](=[NH:21])S.[OH-].[Na+].O>CO>[C:19]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[NH:18])[NH2:21]
Reactant: CNC(=N)S
Reactant: NNC(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N=C(N)NNC(=O)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 96 h
Yield: 104.7 %

Procedure:
The synthesis was carried out according to the method of Example 1-(1). 4-Chlorobenzoic acid hydrazide (34.8 g), methylisothiourea sulfate (115.4 g), sodium hydroxide (17.1 g), water (440 ml) and methanol (700 ml) were used as reagents. The mixture was stirred for 4 days at 60° C. to give 45.4 g of a pale-brown solid which was a mixture of a hydrazide compound and the objective compound.
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])[CH2:6][OH:7].C(N(C(C)C)CC)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(#N)C>[S:25]([O:7][CH2:6][C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:27])(=[O:26])[CH3:24]
Reactant: COc1cc(CO)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(COS(C)(=O)=O)cc(OC)c1OC
Reaction time: 2 h

Procedure:
Combine 3,4,5-trimethoxy-benzyl alcohol (9.0 g, 45.4 mmol), diisopropylethylamine (12.9 g, 100 mmol), and acetonitrile (60 mL). Cool in an ice bath. Add methanesulfonyl chloride (6.76 , 49.0 mmol). After 2 hours, partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the organic layer with 1 M hydrochloric acid solution and them a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.