Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:44].C(N(CC)CC)C.[F:52][C:53]([F:59])([F:58])[S:54](Cl)(=[O:56])=[O:55]>ClCCl>[F:52][C:53]([F:59])([F:58])[S:54]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:32])[CH3:31])[CH2:25][CH2:26]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:44])(=[O:56])=[O:55]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Yield: 76.9 %

Procedure:
In a similar manner to Step 1 of Example 299, 4-hydroxy-7-(1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl)isoindolinone (150 mg, 0.240-mmol) was suspended in dichloromethane (6.0 mL), and the suspension was treated with triethylamine (0.167 mL, 1.20 mmol) and trifluoromethanesulfonyl chloride (0.046 mL, 0.43 mmol) under ice-cooling, followed by purification by preparative thin-layer chromatography (chloroform/methanol=13/1) to obtain 4-trifluoromethanesulfonyloxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (139 mg, yield 77%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:25]([CH3:27])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[CH:25]([O:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([CH3:27])[CH3:26]
Reactant: CCOC(=O)C1(NCc2cccc(C)c2OC(C)C)Cc2ccccc2C1
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: Cc1cccc(CNC2(C(=O)O)Cc3ccccc3C2)c1OC(C)C
Reaction time: 39 h
Yield: 72.2 %

Procedure:
A 100 mL round bottom flask containing 2-(2-isopropoxy-3-methyl-benzylamino)-indan-2-carboxylic acid ethyl ester (365, 360 mg, 0.98 mmol) is charged with 1,4-dioxane (3 mL) and MeOH (3 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1.5 mL) is added followed by the LiOH monohydrate (104 mg, 2.47 mmol). After 39 h, tlc analysis (silica, 50% EtOAc/Heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 15 days, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provided white solid (0.24 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccccc4Cl)CC3)nc2c1
Yield: 89 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 89%). 1H NMR (300 MHz, CDCl3): δ 3.09-3.16 (m, 4H), 3.79-3.90 (m, 6H), 4.10-4.16 (m, 4H), 7.00-7.30 (m, 7H), 7.38-7.66 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([O:16]CC)=[O:15])[N:11]([CH3:19])[N:10]=2)=[CH:5][CH:4]=1)#[N:2].[Li+].[OH-].O.Cl>C1COCC1.CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11]([CH3:19])[N:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1cc(-c2ccc(C#N)cc2)nn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1nc(-c2ccc(C#N)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of ethyl 3-(4-cyanophenyl)-1-methyl-1H-pyrazole-5-carboxylate (70 mg, 274 μmol, Eq: 1.00) in THF (5 ml) and MeOH (1.00 ml) was added LiOH 1M (548 μl, 548 μmol, Eq: 2). The mixture was stirred for ca. 8 h at rt., then treated with water and HCl 1N (pH:3). The mixture was extracted two times with ethyl acetate. The resulting organic layers were combined, washed with Brine and dried over MgSO4, filtered and concentrated to give the desired compound (55 mg, 88.3%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:26][C:27]([F:37])([F:36])[C:28]([NH:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=[O:29].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH:31]([NH:30][C:28](=[O:29])[C:27]([F:37])([F:36])[F:26])[CH2:32]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: O=C(NC1CCNC1)C(F)(F)F
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCC(NC(=O)C(F)(F)F)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 3-(2,2,2-trifluoroacetylamino)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.34 minutes; C23H20Cl2F3N5O3 (542.34); mass spectrum: (M−H)−=541/543/545 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@H:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][S:17][C:18](SC)=[N:19]C#N.[N:24]1C=CC=C[CH:25]=1>>[C:25]([N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@H:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)[C:18](=[NH:19])[S:17][CH3:16])#[N:24]
Reactant: C[C@@H]1CC(=O)NN=C1c1ccc(N)cc1
Reactant: c1ccncc1
Reactant: CSC(=NC#N)SC
Product: CSC(=N)N(C#N)c1ccc(C2=NNC(=O)C[C@H]2C)cc1

Procedure:
A stirred mixture of (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (4 g) and dimethyl cyanodithioiminocarbonate in pyridine is heated to afford (R)-6-(4-(N-cyano-S-methylisothioureido)phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:14])[CH2:11][CH2:12]Br.[C:15]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:14])[CH2:11][CH2:12][N:28]1[CH2:27][CH2:26][N:25]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:30][CH2:29]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: Cc1cccc(C)c1NC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(C)c1NC(=O)CCN1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
To a mixture of N-(2,6-dimethylphenyl)-3-bromopropanamide (1 g, 4.5 mmol) and N-carbobenzyloxypiperazine (1.7 g, 6.8 mmol) in 10 mL of acetone was added potassium carbonate (0.93 g, 6.8 mmol). The mixture was refluxed for 24 hours. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was purified using column chromatography, to provide N-(2,6-dimethylphenyl)-3-(4-carbobenzyloxypiperazinyl)propanamide, a compound of formula (3).
Reaction SMILES: [N+:1]([C:4]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7](Cl)[C:8]([Cl:16])=[N:9]2)([O-:3])=[O:2].[CH3:18][C:19]([CH3:22])([O-:21])[CH3:20].[K+].C1(C)C=CC=CC=1.O>C(O)(C)(C)C>[C:19]([O:21][C:7]1[C:8]([Cl:16])=[N:9][C:10]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=2)[N:6]=1)([CH3:22])([CH3:20])[CH3:18]
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)cc2nc(Cl)c(Cl)nc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1nc2c([N+](=O)[O-])c(Cl)c(Cl)cc2nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To 5-nitro-2,3,6,7-tetrachloroquinoxaline 1608 mg obtained in Example 7(1), was added dropwise a solution of potassium tert-butoxide 644 mg in tert-butanol (15 mL) at −5 to 0° C. The reaction mixture was stirred at 0° C. for 30 min, and toluene 50 mL, 0.1 M sodium dihydrogen phosphate 5 mL, and water were added thereto with shaking. The organic layer was separated, washed with water and saturated saline, and dried over MgSO4. After evaporation, the residue was subjected to column chromato (silica gel/toluene) and crystallized from acetone, to give the title compound (colorless crystal) 1092 mg.
Reaction SMILES: [H-].[Na+].C(#[N:5])C.[NH2:6][C:7]1[N:12]=[C:11]([CH2:13][C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])[N:10]=[C:9]([NH:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[N:8]=1.Cl[CH2:32][CH2:33][CH2:34][N:35]=[C:36]=[O:37]>O1CCOCC1.CN1CCCC1=O>[C:27]([C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:9]2[N:10]=[C:11]([CH2:13][C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[N:12]=[C:7]([NH:6][CH2:32][CH2:33][CH2:34][NH:35][C:36]([NH2:5])=[O:37])[N:8]=2)=[CH:30][CH:29]=1)#[N:28]
Reactant: CC#N
Reactant: N#Cc1ccc(Nc2nc(N)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Reactant: O=C=NCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)nc(NCCCNC(N)=O)n2)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
Sodium hydride (0.00150 mol), ACN (5 ml), compound (1) (0.00135 mol) in 1,4-dioxane (10 ml), and ACN (10 ml) were combined under argon. The solution was stirred for 1 hour. 1-chloro-3-isocyanato-propane (0.00137 mol) was added. The reaction mixture was stirred for 1 hour. 1-methyl-pyrrolidinone (10 ml) was added. The reaction mixture was stirred for 16 hours. Then, the mixture was concentrated. The concentrate was partitioned between DCM/H2O. The resulting solution was filtered, dried over K2CO3, filtered, concentrated and the residue was treated with NH3 in 1,4-dioxane (12 ml, 0.5 M) and heated under pressure at 55° C. The resulting solution was concentrated and further purified by flash column chromatography (eluent: DCM/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 0.12 g (18.9%) of N-[3-[[4-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl) methyl]-1,3,5-triazin-2-yl]amino]propyl]urea (compound 23).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Br[CH2:33][CH2:34][O:35][CH2:36][CH2:37]Br>CN(C)C=O.C(OCC)(=O)C>[O:35]1[CH2:36][CH2:37][N:1]([C@H:2]2[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=3[N+:20]([O-:22])=[O:21])[CH2:6][CH2:7]2)[CH2:33][CH2:34]1
Reactant: NS(=O)(=O)c1ccc(NC[C@H]2CC[C@H](N)CC2)c([N+](=O)[O-])c1
Reactant: BrCCOCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(NC[C@H]2CC[C@H](N3CCOCC3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 451B (0.85 g) and diisopropylethylamine (2.03 mL) in N,N-dimethylformamide (7 mL) was added bis(2-bromoethyl)ether (0.54 g) as a solution in N,N-dimethylformamide (1 mL). The reaction was stirred at room temperature for 1 hour and heated to 70° C. overnight. The reaction was cooled, diluted with ethyl acetate (100 mL), washed with water (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Revleris 120 g) eluting with a gradient of 0.75% to 7.5% over 30 minutes (flow=80 ml/min) gave the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH:14]([NH2:16])[CH3:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11]C)C.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O>O.C(#N)C>[C:29]1(=[O:38])[N:16]([CH:14]([CH2:13][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:1])[CH:5]=2)[CH3:15])[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCOc1ccc(CC(C)N)cc1OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(CC(C)N2C(=O)c3ccccc3C2=O)cc1OC
Reaction time: 0.67 h
Yield: 53.2 %

Procedure:
To a stirred solution of 3-(3,4-diethoxyphenyl)-2-aminopropane (1.95 grams, 10.0 mmol) and sodium carbonate (1.06 grams, 10.0 mmol) in 50 milliliters of water was added N-carbethoxyphthalimide (2.19 grams/10.0 mmol). After 10 minutes the reaction mixture was diluted with 40 milliliters of acetonitrile and the mixture stirred for 40 minutes. The reaction solution was partially concentrated in vacuo to remove the acetonitrile. The resulting mixture of an oil and aqueous layer was extracted with methylene chloride (25 milliliters). The organic extract was dried over sodium sulfate and concentrated in vacuo to afford a crude product which was purified by flash chromatography to afford 1.73 grams (53%) of product as a thick oil which slowly solidified to a white wax: 1H NMR (dmso-d6, 250 MHz) δ 7.7 (m, 4H, Ar), 6.7 (m, 3H, Ar), 4.63 (m, 1H, CH), 3.79 (s, 3H, Ome), 3.73 (s, 3H, OMe), 3.28 (dd, 1H, J=13.8, 9.8 Hz), 3.03 (dd, J=13.8, 6.5 Hz, 1H), 1.54 (d, J=6.9 Hz, 3H); 13C NMR (dmso-d6) δ 168.4, 148.6, 147.4, 133.7, 131.8, 130.9, 122.9, 120.9, 111.1, 55.7, 55.6, 48.6, 39.3, 18.3 Anal. Calcd for C19H19NO2. Theoretical C, 70.14; H, 5.89; N, 4.30. Found C, 70.08; H, 5.83; N, 4.30.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[O:14][CH2:15][CH3:16].CN(C)CCN(C)C.C1CCN([CH:31]=[O:32])CC1>CCCCCC.O1CCCC1>[CH2:15]([O:14][C:8]1[CH:9]=[CH:10][C:11]([CH:31]=[O:32])=[C:12]([F:13])[C:7]=1[F:6])[CH3:16]
Reactant: CCOc1cccc(F)c1F
Reactant: O=CN1CCCCC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(C=O)c(F)c1F
Temperature: -60 °C
Reaction time: 2 h

Procedure:
125 ml of a solution of 0.2 mole of n-butyllithium in hexane is added, at -78° C., to a mixture of 0.2 mole of 2,3-difluorophenetole, 0.2 mole of tetramethylethylenediamine and 400 ml of tetrahydrofuran, and the mixture is stirred for 2 hours at -60° C. A mixture of 0.2 mole of n-formylpiperidine and 20 ml of tetrahydrofuran is added dropwise to this mixture. Warming to -20° C. and working up in the customary manner gives the aldehyde in the form of a colourless solid, melting point 70° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.O.[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(C)=O
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1nc2c(N)nc3c(c2n1NCCCNC(C)=O)CCCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.5 %

Procedure:
A solution of N-(3-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)acetamide (0.220 g, 0.617 mmol) in 15 mL of TFA was treated with platinum (IV) oxide (0.140 g, 0.617 mmol). The mixture was placed under an atmosphere of hydrogen (3.8×105 Pa) and shaken at ambient temperature. After 18 h, the reaction mixture was diluted with CHCl3 (15 mL) and filtered through a pad of CELITE filter agent and rinsed with several portions of CHCl3 (1% TFA). The filtrate was concentrated under reduced pressure to yield an off-white oil. The oil was suspended in a minimum amount of H2O and treated with 50% NaOH solution until the pH of the liquid was 12–13. The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield an off-white solid. The solid was purified by chromatography (SiO2, 15–20% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield a white solid. The solid was recrystallized from MeCN to yield N-(3-{[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)acetamide (0.0633 g) as white crystals. mp 198–200° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.80 (t, J=5.0 Hz, 1H), 6.30 (t, J=6.0 Hz, 1H), 5.78 (s, 2H), 4.61 s, 2H), 3.55 (q, J=7.0 Hz, 2H), 3.12 (q, J=6.7 Hz, 2H), 3.05–3.01 (m, 4H), 2.66 (t, J=5.9 Hz, 2H), 1.78–1.73 (m, 7H), 1.62 (p, J=7.1 Hz, 2H), 1.14 (t, J=7.0 Hz, 3H); 13C NMR (125 MHz DMSO-d6) δ 169.4, 149.9, 149.3, 147.1, 137.6, 122.7, 105.5, 65.7, 63.4, 51.6, 36.8, 32.5, 27.9, 23.9, 23.0, 23.0, 22.5, 15.3; MS (APCI) m/z 361 (M+H)+; Anal. Calcd for C18H28N6O2: C, 59.98; H, 7.83; N, 23.31;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:12]=[CH:11][C:10](=[O:13])[C:9]([C:14]3[N:15]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][Si](C)(C)C)[CH:20]=4)[N:16]=[CH:17][CH:18]=3)=[N:8]2)=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-]>C1COCC1>[C:25]([C:21]1[CH:20]=[C:19]([N:15]2[C:14]([C:9]3[C:10](=[O:13])[CH:11]=[CH:12][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[N:8]=3)=[CH:18][CH:17]=[N:16]2)[CH:24]=[CH:23][CH:22]=1)#[CH:26]
Reactant: C[Si](C)(C)C#Cc1cccc(-n2nccc2-c2nn(-c3ccncc3)ccc2=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cccc(-n2nccc2-c2nn(-c3ccncc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A mixture of 1-Pyridin-4-yl-3-[2-(3-trimethylsilanylethynyl-phenyl)-2H-pyrazol-3-yl]-1H-pyridazin-4-one (example 98, 33 mg, 0.08 mmol) is dissolved in THF (1 ml). Tetrabutylammoniumfluoride trihydrate (51 mg, 0.16 mmol) is added at 0° C. and the reaction mixture is allowed to warm up to ambient temperature within 15 minutes. Stirring is continued for another 1 hour. The reaction mixture is quenched with water and extracted with ethyl acetate. The solvent is removed and the obtained crude product is purified by chromatography on silica gel using EtOAC/MeOH gradient to obtain 22 mg (81% yield) of the product. MS: M=340.1 (M+H)+
Reaction SMILES: CO[C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:23][C:24]([NH2:26])=[O:25])=[C:9]([CH3:22])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:28][NH2:29].C(OCC)(=O)C.O>C(O)C>[NH:28]([C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:23][C:24]([NH2:26])=[O:25])=[C:9]([CH3:22])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:29]
Reactant: NN
Reactant: COC(=O)COc1cccc2c1c(CC(N)=O)c(C)n2Cc1ccccc1
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(CC(N)=O)c2c(OCC(=O)NN)cccc2n1Cc1ccccc1
Yield: 91 %

Procedure:
A mixture of 484 mg (1.3 mmol) of 2-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester (Example 39) and 2 mL of hydrazine in 10 mL of ethanol was heated to maintain reflux for 16 hours, 10 mL of ethanol added, heated an additional 4 hours and cooled. Ethyl acetate and water were added and the insoluble material filtered. The ethyl acetate solution was separated, washed with brine, dried (MgSO4) and concentrated. The residue was combined with he precipitate above co give 435 mg (91% yield) of 4-(2-hydrazino-2-oxoethoxy)-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 207-210° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:45])[CH2:11][N:12]([CH2:14][C:15]1[S:23][C:22]2[C:21](=[O:24])[C:20]([C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[O:26])=[CH:19][N:18]([CH3:36])[C:17]=2[C:16]=1[CH2:37][O:38]CC[Si](C)(C)C)[CH3:13].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:45])[CH2:11][N:12]([CH2:14][C:15]1[S:23][C:22]2[C:21](=[O:24])[C:20]([C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[O:26])=[CH:19][N:18]([CH3:36])[C:17]=2[C:16]=1[CH2:37][OH:38])[CH3:13]
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1COCC[Si](C)(C)C)CC(O)c1cc2ccccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CO)CC(O)c1cc2ccccc2o1
Yield: 78.7 %

Procedure:
A solution of 154 mg of 2-{[[2-(1-benzofuran-2-yl)-2-hydroxyethyl](methyl)amino]methyl}-N-(4-chlorobenzyl)-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 3 mL of 75% TFA in CH2Cl2 is stirred at room temperature for 4 h, then diluted with CHCl3 and added to stirred aq. NaHCO3. The aqueous phase is extracted with 4 portions of CH2Cl2, and the combined organic phases dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica gel using 4% MeOH in CH2Cl2 provides 103 mg of the title compound as a pale yellow solid. Recrystallization from acetonitrile affords white needles.
Reaction SMILES: [CH3:1][CH2:2]O.OS(O)(=O)=O.[NH2:9][C:10]1[C:11]([C:17]([OH:19])=[O:18])=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1>>[NH2:9][C:10]1[C:11]([C:17]([O:19][CH2:1][CH3:2])=[O:18])=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1
Reactant: CCO
Reactant: Nc1cc(Cl)cnc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ncc(Cl)cc1N
Temperature: 120 °C

Procedure:
Absolute EtOH (1.00 mL, d=0.785, 17.0 mmol) and H2SO4 (96%, 0.10 mL, d=1.840, 1.8 mmol) were added to the hydrochloride salt of 3-amino-5-chloropicolinic acid (106) (0.100 g, 0.407 mmol). The mixture was stirred and heated to reflux. The mixture was refluxed (120° C.) for 19 h. The resulting solution was cooled to room temperature, poured over ice (1.0 g), and neutralized to pH 5 with solid Na2 CO3. The resulting mixture was extracted with EtOAc (4×3 mL), the organic layer dried (Na2SO4), and rota-evaporated to dryness, leaving the title compound as an orange solid, 68.6 mg (84.0%), mp 139.5°-142.5° C. (Lit., 165°-6° C., McCaustland and Cheng, J. Heterocycl. Chem. 7:467 (1970)); 1H NMR (CDCl3): δ1.44 (t, J=6.9 Hz, 3H), 4.45 (q, J=6.9 Hz, 3H), 5.84 (bs, 2H), 7.05 (d, J=1.5 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H).