Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si]([C:11]#[C:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH2:18])=[O:17])(C)C.O.CCOC(C)=O>CO>[C:12]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH2:18])=[O:17])#[CH:11]
Reactant: C[Si](C)(C)C#Cc1cccc(C(N)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cccc(C(N)=O)c1
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
Potassium carbonate (1.84 g, 13.3 mmol) was added to a stirred solution of 3-((trimethylsilyl)ethynyl)benzamide (130) (1.45 g, 6.66 mmol) in MeOH (15 mL) at room temperature. The resulting suspension was stirred for 30 minutes then water (100 mL) and EtOAc (100 mL) were added. The resulting precipitate was collected via filtration and after air drying this was suspended in a 1:1 mix of acetone and methanol (15 mL). After sonication the resulting suspension was filtered to give the title compound (I31) (335 mg, 35%) which was used without additional purification.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][CH2:4][CH:3]1[CH2:19][Cl:20].[Cl:21]N1C(=O)CCC1=O>C(Cl)Cl>[ClH:20].[Cl:21][C:11]1[CH:10]=[CH:9][C:8]2[N:2]([CH3:1])[CH:3]([CH2:19][Cl:20])[CH2:4][N:5]=[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]=2[CH:12]=1
Reactant: CN1c2ccccc2C(c2ccccc2)=NCC1CCl
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CN1c2ccc(Cl)cc2C(c2ccccc2)=NCC1CCl
Product: Cl
Yield: 117.2 %

Procedure:
4.1 g of 1-methyl-2-chloromethyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine and 1.94 g of N-chlorosuccinimide were heated under reflux in 50 ml methylenechloride for 24 hours. The solvent was then distilled off in a vacuum, the crude product was taken up in ether and reacted with an isopropanol solution of hydrogen chloride. There were obtained 3 g of 7-chloro-1-methyl-2-chloromethyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine hydrochloride. The product was identical with that of Example 4.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.Cl>C(O)C.O>[Cl:8][C:7]1[C:2]([NH2:1])=[C:3]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[N:4]=[CH:5][N:6]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: Nc1c(Cl)ncnc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)ncnc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To a stirring slurry of 5-amino-4,6-dichloropyrimidine (3 g, 18.29 mmol) and indoline (2.057 mL, 18.29 mmol) in ethanol (7 mL) and water (43 mL) was added concentrated aqueous HCl (600 μL) and the mixture was refluxed for 3 h and left to stir at room temperature overnight. The reaction mixture was extracted with ethyl acetate, washed with water, brine, dried over MgSO4 and solvent evaporated. The resulting residue was triturated in 25% ethyl acetate in hexanes for 1 h then filtered to afford title compound 105 (1.55 g, 34%) as a tan solid. LRMS (ESI): (calc) 246.07. (found) 247.2 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1F)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccccc1F)C2
Yield: 69.2 %

Procedure:
A mixture of 7-(2-fluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.35 g), aminoguanidine hydrochloride (0.16 g), concentrated hydrochloric acid (0.21 ml), water (0.21 ml) and ethanol (40 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate, and to the mixture was added sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid (3 ml), and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give 7-(2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 59) (0.33 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Br:10]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:10])=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1nc(N)nc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution containing 4.31 g (34.75 mmol) of 2-amino-4,6-dimethylpyrimidine (2) in 150 mL of acetonitrile were added 6.15 g (52.12 mmol) of N-bromosuccinimide. The reaction mixture was stirred at room temperature under argon atmosphere for 3 h. The formed precipitate was filtered and dried to afford the expected product as a white solid: yield 5.93 g (83%). 1H-NMR (CDCl3) δ 5.19 (br, 2H), 2.44 (s, 6H); 13C-NMR (CDCl3) δ 166.28, 160.73, 109.60, 24.70.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][CH:11]=1.C(O)(=O)C.CO>O>[NH:5]([CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:14][CH:15]=1)[C:2]([NH2:3])=[O:1]
Reactant: CC1NC(=O)NN=C1c1ccc(NCCCN)cc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC1NC(=O)NN=C1c1ccc(NCCCNC(N)=O)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 32.1 %

Procedure:
Potassium cyanate (0.516 g) was added to a solution of 6-[4-(3-aminopropylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.66 g), acetic acid (0.382 g) and methanol (10 ml) in water (20 ml), and the mixture was stirred for 60 hours at room temperature. The resulting precipitates were collected by filtration, washed with water and recrystallized from 80% aqueous ethanol to give 6-[4-(3-ureidopropylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.62 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:9]([CH2:20][CH2:21]/[CH:22]=[CH:23]/[N+:24]([O-:26])=[O:25])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.O.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:9]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:20][CH2:21][C@@H:22]([C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([F:34])[C:40]=1[F:41])[CH2:23][N+:24]([O-:26])=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC/C=C/[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](C[N+](=O)[O-])c1cccc(F)c1F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 87.4 %

Procedure:
A solution of benzyl (2R,5E)-2-[bis(tert-butoxycarbonyl)amino]-6-nitrohex-5-enoate (34.0 g, 73.2 mmol), 2,3-difluorophenylboronic acid (28.9 g, 183.0 mmol) and water (4.62 mL, 256.2 mmol) in dioxane (240 mL) was degassed with argon for 15 min. To this solution was added sodium bicarbonate (3.08 g, 36.6 mmol), (S)-BINAP (1.28 g, 2.05 mmol) and acetylacetanotobis(ethylene)rhodium(I) (0.472 g, 1.83 mmol). The mixture was stirred at RT for 2 min then heated to 35° C. After 4 h, 255 mg of (S)-BINAP and 94 mg of acetylacetanotobis(ethylene)rhodium(I) were added. After an additional 2 h the reaction was diluted with DCM/NaHCO3, the layers separated and the aqueous phase was backwashed with another portion of DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated to give a residue that was purified by silica gel chromatography (5%→60% ethyl acetate/hexanes) to give the title compound (37.0 g, 87%) contaminated with ˜5% 5R isomer. MS 379.1 (M+1−2Boc).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:27])[C:13]([NH:15][C@H:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][C:20]([OH:26])=[CH:21][CH:22]=4)[CH2:17]3)=O)=[CH:11][C:5]=2[CH2:4][O:3]1.N(CCO)(CCO)CCO.O>O1CCCC1>[CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:27])[CH2:13][NH:15][C@H:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][C:20]([OH:26])=[CH:21][CH:22]=4)[CH2:17]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H](O)C(=O)N[C@H]3CCc4ccc(O)cc4C3)ccc2O1
Solvent: C1CCOC1
Solvent: OCCN(CCO)CCO
Solvent: O
Product: CC1(C)OCc2cc([C@@H](O)CN[C@H]3CCc4ccc(O)cc4C3)ccc2O1
Yield: 84.7 %

Procedure:
(-)-(2R)-2-(2,2-Dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (686 mg) was dissolved in 50 ml of tetrahydrofuran, 3.58 ml of 2 M borane-dimethylsulfide complex in tetrahydrofuran was added, and the mixture was heated under reflux for 3 hours. Then, a solution of 1.34 g of triethanolamine in 5.0 ml of tetrahydrofuran was added, and the mixture was again heated under reflux for 15 hours. After cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was recrystallized from ethyl acetate to give 560 mg of (-)-(1R)-1-(2,2-dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)-2-[((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino]ethanol having a melting point of 156 to 158° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35](O)=[O:36]>CN(C=O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:35]([C:27]4[NH:26][C:34]5[C:29]([CH:28]=4)=[CH:30][CH:31]=[CH:32][CH:33]=5)=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc5ccccc5[nH]4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1H-indole-2-carboxylic acid as starting compounds. The crude product is treated with DMF, the solids are removed by filtration, and the solvent is removed under reduces pressure. The resulting solid is purified by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH:29]1[CH:30]=[CH:31]C2N(O)N=[N:35][C:33]=2[CH:34]=1.CCN=C=NCCCN(C)C.Cl.Cl.[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:59]NC1CCNCC1>CN(C=O)C.O>[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:59][CH:29]1[CH2:30][CH2:31][N:35]([C:16](=[O:18])[CH2:15][C:14]([NH:13][C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:19])[CH2:33][CH2:34]1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Reactant: On1nnc2ccccc21
Reactant: Brc1ccccc1SNC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCC(Sc2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)nc1
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a stirred solution of N-(6-phenyl-pyridin-3-yl)-malonamic acid (0.07 g, 0.00024 mole) in DMF (1 mL) was added DIPEA (0.153 g, 0.00120 mole), HOBt (0.039 g, 0.00029 mole) and EDCI.HCl (0.055 g, 0.00029 mole). After 2 minutes (2-bromo-phenylsulfanyl)-piperidin-4-yl-amine hydrochloride (0.088 g, 0.00028 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 73.2 mg (60%) of 3-[4-(2-bromo-phenylsulfanyl)-piperidin-1-yl]-3-oxo-N-(6-phenyl-pyridin-3-yl)-propionamide. LC-MS purity: 510.08 (M+1)+, 93.64%, 1H NMR (DMSO-d6): δ 10.5 (s, 1H), 8.8 (d, 1H), 8.2 (d, 1H), 8.1 (d, 2H), 8.0 (d, 1H), 7.84-7.7 (m, 2H), 7.7 (t, 1H), 7.54-7.36 (m, 4H), 4.3 (d, 1H), 3.9 (d, 1H), 3.8-3.7 (m, 1H), 3.6 (s, 2H), 3.3-3.2 (m, 1H), 3.0-2.9 (m, 1H), 2.0 (t, 2H), 1.6-1.5 (m, 1H), 1.5-1.4 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH2:12][CH3:13])[C:3]=1[F:14].[Cu][C:16]#[N:17].C(OCC)(=O)C.[NH4+]>CN(C)C=O>[CH2:12]([O:11][C:4]1[C:3]([F:14])=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH3:10])[C:16]#[N:17])[CH3:13]
Reactant: CCOc1ccc(Br)c(F)c1OCC
Reactant: N#C[Cu]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(C#N)c(F)c1OCC
Temperature: 155 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution of 1-bromo-3,4-diethoxy-2-fluorobenzene (12.0 g, 45.6 mmoL) in N,N-dimethylformamide (DMF) (60 mL), copper (I) cyanide (6.8 g, 68.3 mmoL) was added at room temperature and then stirred at 155° C. for 3 hours. After ice cooling the reaction solution, ethyl acetate and 28% aqueous ammonium were added thereto to separate the organic layer. This organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated. The residue was purified by silica gel column chromatography (n-hexane, ethyl acetate) to give 9.0 g of the captioned compound (yield: 94.3%).
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH2:9][S:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[O-:14]I(=O)(=O)=O.[Na+]>O.CO>[C:1]([Si:5]([CH3:12])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][S:10]([CH3:11])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCCCO[Si](C)(C)C(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of tert-butyldimethyl(3-(methylthio)propoxy)silane (0.1 mol) in water/MeOH (3:2, 500 mL) at 0° C. was added sodium (meta)periodate (˜30 g). The reaction mixture was stirred first at 0° C. for 20 hours, then at room temperature for 3 hours. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to remove the most of the organic solvent. The aqueous residue was then extracted with CHCl3 (2×) and the combined organic extracts were dried with anhydrous sodium sulfate. The organic phase was decanted and concentrated to yield the title compound as an oil which solidified to provide a white solid upon standing (17.65 g).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10](=[O:19])[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)[CH:8]=[CH:9][C:2]=12.Br.C(=O)(O)[O-:22].[Na+]>CS(C)=O.O>[N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10](=[O:19])[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[O:22])[CH:8]=[CH:9][C:2]=12
Reactant: O=C([O-])O
Reactant: Cc1cccc(CC(=O)c2ccc3nsnc3c2)n1
Agent: Br
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(C(=O)C(=O)c2ccc3nsnc3c2)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1-Benzo[1,2,5]thiadiazol-5-yl -2-(6-methyl-pyridin-2-yl)-ethanone (5.88 g, 21.8 mmol) was dissolved in dimethyl sulfoxide (50 ml) heated to 60° C. Hydrogen bromide (7.1 ml of a 48% solution in water) was added dropwise and the reaction stirred for 3 hours at 60° C. The cooled reaction was poured into water (100 ml) and the pH adjusted to pH 8 with saturated sodium bicarbonate solution. The organic product was extracted into ethyl acetate (3×100 ml), dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure (5.19 g, 84%); 1H NMR (250 MHz, CDCl3) δ: 2.47 (3H, s), 7.40 (1H, d), 7.85 (1H, t), 8.06 (1H, d), 8.15 (1H, d), 8.28 (1H, d), 8.45 (1H, s); m/z(API) 284 (M+H+, 100%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)(=[O:11])[CH3:10].[Br:18][C:19]1[C:20]([OH:28])=[C:21]([C:24](OC)=[O:25])[S:22][CH:23]=1>O1CCCC1>[Br:18][C:19]1[C:20]([OH:28])=[C:21]([C:24](=[O:25])[CH2:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[S:22][CH:23]=1
Reactant: CC(=O)N1CCOCC1
Reactant: COC(=O)c1scc(Br)c1O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)N1CCOCC1)c1scc(Br)c1O
Temperature: 0 °C
Yield: 138.2 %

Procedure:
An oven-dried 100 mL round-bottom flask was charged with a magnetic stirring bar, tetrahydrofuran (5 mL) and lithium diisopropylamide (2.0M in hexanes, 6.7 mL, 13.5 mmol). The reaction mixture was magnetically stirred and cooled to 0° C. under argon gas. A solution of N-acetylmorpholine (6.75 mmol) in tetrahydrofuran (1 mL) was added, and the reaction was stirred at 0° C. for 1 hour. A solution of methyl 4-bromo-3-hydroxythiophene-2-carboxylate (4.22 mmol) in tetrahydrofuran (2 mL) was added dropwise over 5 minutes and the reaction was allowed to warm to room temperature overnight. The reaction was quenched by the addition of aqueous 10% hydrochloric acid solution (20 mL). The resulting solution was transferred to a separatory funnel, diluted with water (80 mL), and extracted three times with dichloromethane (100 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1-(4-bromo-3-hydroxythiophen-2-yl)-3-morpholinopropane-1,3-dione (1.95 g, 5.83 mmol, 138% yield) as a brown solid.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH:12]([O:18]C(=O)C)[CH2:13][O:14]C(=O)C)=[O:9])=[C:6]([I:22])[C:5]([C:23]([NH:25][CH2:26][CH:27]([O:33]C(=O)C)[CH2:28][O:29]C(=O)C)=[O:24])=[C:4]([I:37])[C:3]=1[NH:38][C:39]([NH:41][C:42]1[C:47]([I:48])=[C:46]([C:49]([NH:51][CH2:52][CH:53]([O:59]C(=O)C)[CH2:54][O:55]C(=O)C)=[O:50])[C:45]([I:63])=[C:44]([C:64]([NH:66][CH2:67][CH:68]([O:74]C(=O)C)[CH2:69][O:70]C(=O)C)=[O:65])[C:43]=1[I:78])=[O:40].[OH-].[Na+]>O.CO>[I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH:12]([OH:18])[CH2:13][OH:14])=[O:9])=[C:6]([I:22])[C:5]([C:23]([NH:25][CH2:26][CH:27]([OH:33])[CH2:28][OH:29])=[O:24])=[C:4]([I:37])[C:3]=1[NH:38][C:39]([NH:41][C:42]1[C:47]([I:48])=[C:46]([C:49]([NH:51][CH2:52][CH:53]([OH:59])[CH2:54][OH:55])=[O:50])[C:45]([I:63])=[C:44]([C:64]([NH:66][CH2:67][CH:68]([OH:74])[CH2:69][OH:70])=[O:65])[C:43]=1[I:78])=[O:40]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)Nc2c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c2I)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 40 °C
Reaction time: 6 h

Procedure:
N,N'-bis[2,4,6-triiodo-3,5-bis(2,3-diacetoxypropylaminocarbonyl)phenyl]-urea (4.0 g, 2.26 mmol) was dissolved in a 1:1 mixture of water and methanol (25 ml) containing NaOH (1.44 g, 36 mmol). After stirring for 6 h at 40° C., the solution was treated with a strongly acidic ion exchange resin (Amberlyst 15), the solvent was separated and evaporated to give pure product. Yield: 3.24 g (100%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][N:4]=1)[NH2:2].[CH:18]([O-])([O-])OCC>>[N+:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]3[N:4]([CH:18]=[N:2][N:1]=3)[CH:5]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: NNc1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Reactant: CCOC([O-])[O-]
Product: O=[N+]([O-])c1ccc(-c2ccc3nncn3c2)cc1

Procedure:
2-Hydrazino-5-(4-nitrophenyl)pyridine is treated with ethyl orthoformate to give the product of the Example.
Reaction SMILES: [Li+].C[CH:3]([N-:5]C(C)C)C.[C:9]([N:16]1[CH2:19][CH:18]([CH2:20][CH2:21]I)[CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1>>[C:9]([N:16]1[CH2:19][CH:18]([CH2:20][CH2:21][CH:24]2[CH2:23][CH2:27][CH2:3][NH:5][C:25]2=[O:26])[CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CC(CCI)C1
Reactant: CC(C)[N-]C(C)C
Reactant: C1CCOC1
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CC(CCC2CCCNC2=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 135 (for preparation see; D. H. Hua, et. al., JOC, 55, 3682, 1990) (0.19 g, 1.2 mmol) in THF (3.9 mL) at -78° C. was added LDA (0.58 mL, 1.2 mmol, 2.0M/heptane/THF/ethylbenzene) dropwise. After 15 min 134 (0.30 g, 0.96 mmol) in THF (3.5 mL) was added dropwise. After stirring 1.0 h, the reaction was quenched with CH3OH (7.5 mL) and the resulting solution warmed to ambient temperature. The solution was then diluted with EtOAc and then washed with H2O, 5% KHSO4, sat. NaHCO3, and brine, dried (MgSO4), and concentrated to give 136 (0.27 g) as a white solid. Rf 0.25 (silica, 2:1 CH2Cl2 /acetone). 1H ITMR (400 MHz, CDCl3) δ 5.81 (bs, 1H), 3.95 (m, 2H), 3.54 (m, 2H), 3.10 (m, 2H), 2.47 (m, 1H), 2.26 (m, 1H), 2.00-1.40 (m, 8H), 1.43 (s, 9H). ##STR60##
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=3)[N:8]=[C:7]([C:24]#[N:25])[C:6]=2[N:26]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN(C=O)C.CO>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:8]=[C:7]([C:24]#[N:25])[C:6]3[N:26]=[C:3]([CH2:2][N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[NH:4][C:5]=3[CH:10]=2)=[CH:12][C:13]=1[C:20]([F:23])([F:22])[F:21])[CH3:19]
Reactant: CN1CCNCC1
Reactant: CCOc1ccc(-c2cc3[nH]c(CCl)nc3c(C#N)n2)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1ccc(-c2cc3[nH]c(CN4CCN(C)CC4)nc3c(C#N)n2)cc1C(F)(F)F
Temperature: 120 °C
Yield: 34 %

Procedure:
2-Chloromethyl-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg, 0.053 mmol) was dissolved in DMF and N-methyl piperazine (26 mg, 0.26 mmol) was added. The mixture was heated to 120° C. for five minutes in a Smith Creator microwave. Mixture was diluted with methanol (4 ml) and loaded onto an SCX cartridge. Cartridge was washed three times with methanol (5 ml) then eluted with 2M methanolic ammonia. Methanolic ammonia was removed by evaporation under reduced pressure then mixture was prep HPLC purified to afford 8 mg of 6-(4-ethoxy-3-trifluoromethyl-phenyl)-2-(4-methyl-piperazin-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile as a white solid. 1H NMR (MeOH) δ 8.28-8.20 (m, 2H), 8.13 (s, 1H), 7.26 (d, 1H), 4.22 (q, 2H), 3.92 (s, 2H), 2,67 (m, 8H), 2.38 (s, 3H), 1.45 (t, 3H). MS m/z 445.5 (M+1).