Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][OH:2].[CH3:3][C:4]1[CH:13]=[C:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH:25]=[CH:26][CH:27]=[C:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1>O1CCCC1>[CH3:3][C:4]1[CH:13]=[C:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH2:25][CH:26]([NH:1][OH:2])[CH:27]=[C:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)(=[O:23])=[O:24])=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)C=CC=C3CCSCC3)cc2)c2ccccc2n1
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(S(=O)(=O)CC(C=C3CCSCC3)NO)cc2)c2ccccc2n1
Reaction time: 54 h
Yield: 63 %

Procedure:
A 50% aqueous solution of hydroxylamine (2 mL) was added to a solution of 0.18 g (0.40 mmol) of 2-methyl-4-{4-[3-(tetrahydrothiopyran-4-ylidene)-1-propene-1-sulfonyl]phenoxymethyl}quinoline obtained in the same manner as Example 9 (9-1) and (9-2) in tetrahydrofuran (5 mL) at room temperature and stirred for 54 hours. After the reaction was completed, the solvent was removed under a reduced pressure, the residue was extracted with chloroform, and the organic layer was dried over magnesium sulfate. After drying, the solution was filtered and the filtrate was concentrated under a reduced pressure, and the obtained residue was subjected to column chromatography on silica gel (silica gel 4 g, developing solvent; chloroform:methanol=20:1) to obtain 0.12 g (yield 63%) of N-{2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl]-1-(tetrahydrothiopyran-4-ylidenemethyl)ethyl}hydroxylamine (III-17) as a white crystal. Its physical properties are shown below.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH2:20][CH2:19][CH:18]([CH2:21]I)[CH2:17][CH:16]=1.[CH3:23][N:24]1[C:28](=[O:29])[CH2:27][NH:26][C:25]1=[O:30].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:26]2[CH2:27][C:28](=[O:29])[N:24]([CH3:23])[C:25]2=[O:30])[CH2:17][CH:16]=1
Reactant: Clc1c(C2=CCC(CI)CC2)ccc2c1nnn2CC1CC1
Reactant: CN1C(=O)CNC1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN1C(=O)CN(CC2CC=C(c3ccc4c(nnn4CC4CC4)c3Cl)CC2)C1=O
Temperature: 85 °C
Reaction time: 3 h

Procedure:
4-Chloro-1-(cyclopropylmethyl)-5-[4-(iodomethyl)cyclohex-1-en-1-yl]-1H-benzotriazole (0.12 g, 0.29 mmol), 3-methylimidazolidine-2,4-dione (67 mg, 0.58 mmol, 2 equiv) and potassium carbonate (0.20 g, 1.5 mmol, 5 equiv) were combined in acetonitrile (5 mL) and placed into a preheated oil bath at 85° C. for 3 hours. Additional 3-methylimidazolidine-2,4-dione (0.13 mg, 1.2 mmol, 4 equiv) and cesium carbonate (0.48 g, 1.5 mmol, 5 equiv) were added and the mixture was heated at 85° C. for an additional 45 minutes. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (50 mL, aqueous saturated) and extracted with ethyl acetate (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound as a colorless foam: 1H-NMR (400 MHz, CDCl3) δ 7.41 (1H, d, J=8.5 Hz), 7.30 (1H, d, J=8.5 Hz), 5.77-5.72 (1H, m), 4.51 (2H, d, J=7.1 Hz), 3.94 (2H, s), 3.47 (1H, dd, J=14.0, 7.4 Hz), 3.40 (1H, dd, J=14.0, 7.2 Hz), 3.05 (3H, s), 2.53-2.38 (2H, m), 2.33 (1H, br d, J=17.7 Hz), 2.15-1.87 (3H, m), 1.61-1.51 (1H, m), 1.45-1.34 (1H, m), 0.69-0.64 (2H, m), 0.51-0.47 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 414.1702 [(M+H)+; calculated for C21H25ClN5O2: 414.1691].
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([CH3:28])([S:19]([C:22]1[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=1)(=[O:21])=[O:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[C:10]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:28])([S:19]([C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)(=[O:21])=[O:20])[C:4]([OH:29])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(-c2ccccc2)cc1)S(=O)(=O)c1nccn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1ccnc1S(=O)(=O)C(C)(Cc1ccc(-c2ccccc2)cc1)C(=O)O

Procedure:
3-Biphenyl-4yl-2-methyl-2(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid was prepared according to the general method as outlined in example 9. Starting from 3-biphenyl-4-yl-2-methyl2-(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid ethyl ester (5.Og, 11.9 mmol), ethanol (15 mL) and 10 N sodium hydroxide (10 mL). Yield 2.8g (61%); brown solid mp 119-122° C.; MS 385.2 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O-])=[O:17])[CH2:11][CH2:10]1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].S([O-])([O-])(=O)=O.[Mg+2]>CCOCC.C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1
Reactant: O=C([O-])CC1CCC(CCC2OCCCO2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: OCCC1CCC(CCC2OCCCO2)CC1
Temperature: -65 °C
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
Toluene (450 ml) was added to the above ethyl 2-(4-(1,3-dioxan-2-ylethyl)cyclohexylethanoate (30.2 g, 106 mmol) in a nitrogen gas atmosphere, followed by cooling the mixture down to -65° C., dropwise adding to the solution, a toluene solution of diisobutylaluminum hydride (1.01 mol/l) 120 ml (121 mmol), stirring the mixture at the same temperature for 45 minutes, dropwise adding a saturated aqueous solution of ammonium chloride (33 ml), heating the mixture up to room temperature, adding ether (100 ml) to the reaction solution, stirring the mixture at the temperature for 1.5 hours, adding magnesium sulfate (10 g), stirring the mixture for one hour, filtering off the reaction solution, washing the filtrate with water, drying over magnesium sulfate, and distilling off the solvent, to obtain 2-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)ethanol (22.0 g, 91.5 mmol). Yield: 86.3%.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([C:5](O)=[O:6])[C@@H:3]1[CH:8]=[C:9]1[CH2:11][CH2:10]1.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C@@H:4]([C:5]([Cl:15])=[O:6])[C@@H:3]1[CH:8]=[C:9]1[CH2:11][CH2:10]1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@@H](C=C2CC2)[C@@H]1C(=O)O
Solvent: c1ccccc1
Product: CC1(C)[C@@H](C=C2CC2)[C@@H]1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.1 gm of dl-trans 3,3-dimethyl-2-cyclopropylidenemethyl-1-cyclopropanecarboxylic acid were introduced into 5 cc of benzene and 0.55 cc of thionyl chloride were added over about 15 minutes. Next, the reaction mixture was agitated for 3 hours at room temperature, after which the solvent and the excess thionyl chloride were eliminated by distillation under reduced pressure to obtain 1.2 gm of raw dl-trans 3,3-dimethyl-2-cyclopropylidenemethyl-1-cyclopropanecarboxylic acid chloride. The product was utilized as such for the next step.
Reaction SMILES: [Br:1]Br.[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:7]1[S:3][C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:5][CH:6]=1
Reactant: BrBr
Reactant: CCOC(=O)C1CCN(c2nccs2)CC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(c2ncc(Br)s2)CC1
Yield: 97.4 %

Procedure:
Bromine (0.14 mL, 2.7 mmol) was weighed into a vial and then diluted with acetic acid (1 mL). This solution was added dropwise (over 10 minutes) to a solution of ethyl 1-(1,3-thiazol-2-yl)piperidine-4-carboxylate (650 mg, 2.7 mmol) in acetic acid (12.5 mL). The mixture was then diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 840 mg (2.63 mmol, 97% yield) of ethyl 1-(5-bromo-1,3-thiazol-2-yl)piperidine-4-carboxylate as a green oil.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9]CC)=O.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[CH:22][C:23](=[O:25])[CH3:24]>>[O:9]=[C:7]1[CH2:24][C:23](=[O:25])[CH2:22][CH:21]([C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)[CH:6]1[C:5]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1ccco1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C1C(=O)CC(=O)CC1c1ccco1

Procedure:
To a solution of sodium ethoxide (from 2.3 g. sodium and dry ethanol 35 ml.) was added slowly diethyl malonate (14 g.). After the addition the mixture was heated under reflux for 1 minute, cooled and then treated with 4-(2-furyl)-3-buten -2-one (13 g.). After heating under reflux for 17 hrs. and cooling, the precipitated sodium enolate salt (of formula III) was collected by filtration, washed with acetone and dissolved in water. The solution was acidified with 2N-sulphuric acid (to convert the enolate salt to the corresponding dione II) and extracted with dichloromethane. After washing the organic layer with water and drying over sodium sulphate, removal of solvents under reduced pressure afforded ethyl 2,4-dioxo-6-(2-furyl)-cyclohexanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@:12]2([CH3:15])[CH2:14][O:13]2)=[O:11])=[CH:5][CH:4]=1.C1COCC1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1>C(=O)=O.CC(C)=O>[OH:13][C@@:12]([CH3:15])([CH2:14][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: COc1ccc(NC(=O)[C@]2(C)CO2)cc1
Reactant: COc1ccc([Mg]Br)cc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C[C@](C)(O)C(=O)Nc2ccc(OC)cc2)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
To a 500 mL single-necked round-bottomed flask fitted with a stirring bar, rubber stopper and a nitrogen inlet was added (S)—N-(4-methoxyphenyl)-2-methyloxirane-2-carboxamide (1.00 g, 4.83 mmol) and anhydrous THF (50 mL). The solution was cooled to −78° C. in dry ice-acetone bath. 4-Methoxyphenylmagnesium bromide solution (14.50 mL of 0.5 M THF solution, 7.25 mmol) was added dropwise with stirring at −78° C. The resulted solution was stirred at −78° C. for 30 minutes and then at room temperature for 3 hours. The reaction was quenched by adding 20 mL of saturated NH4Cl solution at 0° C. EtOAc (3×30 mL) was added to extract the solution. The organic layers were separated, washed with brine (20 mL) and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, EtOAc/hexanes=1/1 v/v) to give a white solid product, (S)-2-hydroxy-N,3-bis(4-methoxyphenyl)-2-methylpropanamide (6c), 0.60 g, 39.5% yield.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][C:18]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[NH4+:37].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:37][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][C:18]3([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:6]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3cccnc3c2n1CC1(O)CCCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To a solution of 1-[(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol (1.43 g, 4.41 mmol) in chloroform (20 mL) at rt was added m-chloroperbenzoic acid (m-CPBA, 70%, 2.17 g, 8.82 mmol). After 1.5 h, the solution was was cooled to 0° C. and concentrated ammonium hydroxide (5 mL) was added. After 3 min, p-toluenesulfonyl chloride (TsCl, 0.920 g, 4.85 mmol) was added in portions. After 1 h, the reaction mixture was filtered and the filter cake was washed with chloroform. The filtrate was washed with saturated aqueous sodium bicarbonate (50 mL) and dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an orange foam which was purified twice by HPFC (silica gel, gradient elution with 0-25% CMA/CHCl3 where CMA is a solution comprised of 80% CHCl3, 18% MeOH, and 2% conc. NH4OH; followed by 0-30% CMA/CHCl3). The appropriate fractions were concentrated and triturated with acetonitrile. The solid was isolated by filtration and dried at 100° C. under vacuum to yield 1-[(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol (567 mg, 38%) as a white powder, mp 209.0-211.0° C. Anal. Calcd for C19H25N5O.0.2H2O C, 66.35; H, 7.47; N, 20.36. Found: C, 66.62; H, 7.34; N, 20.05.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[N:10]3[C:11](=[N:16][C:17]([CH3:18])=[C:9]3[C:8]1=[O:19])[CH:12]=[CH:13][CH:14]=2.C(N(CC)CC)C.[F:27][C:28]([F:35])([F:34])[CH2:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:18][C:17]1[N:16]=[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[N:10]2[C:9]=1[C:8](=[O:19])[N:7]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:30]([CH2:29][C:28]([F:35])([F:34])[F:27])(=[O:32])=[O:31]
Reactant: Cc1nc2cccc3n(CCCCCN)c(=O)c1n23
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2cccc3n(CCCCCNS(=O)(=O)CC(F)(F)F)c(=O)c1n23
Yield: 65.4 %

Procedure:
To a solution of 1.630 g (6.31 mmol) of 1-[5-(amino)pentyl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 1.32 ml (9.47 mmol) of triethylamine in 30 ml of methylene chloride was added, while stirring under ice-cooling, 1.38 g (7.56 mmol) of 2,2,2-trifluoroethanesulfonylchloride. The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 1.669 g of the desired compound (65.4%, pale brown solid substance).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7]([C:10](Cl)=[O:11])[N:8]=[CH:9][N:4]2[CH:3]=1.[H-].[Cl-].[NH4+]>>[Br:1][C:2]1[S:6][C:5]2=[C:7]([CH:10]=[O:11])[N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(Cl)c1ncn2cc(Br)sc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: O=Cc1ncn2cc(Br)sc12
Temperature: -40 °C
Reaction time: 6 h
Yield: 31.1 %

Procedure:
A solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid chloride (103 mg, 0.39 mmol) in diglim (10 ml) was cooled to −78° C. A solution of tri-t-butoxyaluminumlithium hydride(237 mg, 0.94 mmol) in diglim (6 ml) was added dropwise to the cooled solution, and, while gradually raising the temperature to −40° C., the mixture was stirred for 6 hr. After the completion of the reaction, a saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate (7 ml×3). The organic layer was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:methanol=60:1) to give 2-bromoimidazo[5,1-b]thiazole-7-carbaldehyde (28 mg, 31%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]([O:6][C:7]2[C:8]([NH:23][C:24]3[S:28][N:27]=[C:26]([CH2:29][CH:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[N:25]=3)=[N:9][CH:10]=[C:11]([S:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]4[CH:20]=[CH:21][S:22][C:15]=34)[CH:12]=2)=[CH:4][CH:3]=1.CO.C(Cl)[Cl:48].[ClH:50]>O1CCOCC1>[ClH:48].[ClH:50].[ClH:48].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:8]([NH:23][C:24]3[S:28][N:27]=[C:26]([CH2:29][CH:30]4[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)[N:25]=3)=[N:9][CH:10]=[C:11]([S:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]4[CH:20]=[CH:21][S:22][C:15]=34)[CH:12]=2)=[CH:43][CH:44]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2nsc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccc(F)cc3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Fc1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(CC3CCNCC3)ns2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A 10 mL round-bottomed flask was charged with tert-butyl 4-((5-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)methyl)piperidine-1-carboxylate (52.2 mg, 0.0802 mmol) and a 1:1 mix of methanol and CH2Cl2 (4 mL). 4N HCl in dioxane (2 mL) was added and the reaction stirred at room temperature for 10 minutes. The solvent was removed to afford crude 3-(4-fluorophenoxy)-N-(3-(piperidin-4-ylmethyl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine trihydrochloride (52.9 mg, 100%).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.CS(O)(=O)=O.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[CH2:30]2.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:26][C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][C:31](=[O:36])[CH2:30]4)=[N:5]2)=[CH:10][CH:11]=1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Agent: CS(=O)(=O)O
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)CC(=O)N4)nn12
Yield: 5.6 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (75.0 mg, 0.000261 mol), Methanesulfonic acid (0.03388 mL, 0.0005220 mol) and [B] 5-Amino-1,3-dihydro-indol-2-one (77.3 mg, 0.000522 mol) were dissolved in 1-Methoxy-2-propanol (0.74 mL, 0.0076 mol) and the reaction was irradiated at 300 watts, 200° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 5.40 mg of 5-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-1,3-dihydro-indol-2-one as a lyophilized powder. (M+H)=371.9. 1H NMR (400 MHz, DMSO, d6) δ 10.19 (s, 1H), 9.25 (s, 1H), 8.91 (s, 1H), 7.78 (d, 1H, J=7.53 Hz), 7.74 (s, 1H), 7.47 (t, 1H, J=7.53 Hz), 7.39 (d, 1H, J=7.88 Hz), 7.23 (d, 1H, J=8.09 Hz), 7.13 (t, 1H, J=7.28 Hz), 6.90 (dd, 2H, J=4.61, 6.41 Hz), 6.64 (d, 1H, J=8.37 Hz), 3.78 (s, 3H), 3.38 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH3:27]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:26]([CH2:25][CH2:24][O:23][CH3:22])[CH3:27])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CNCCOC
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: COCCN(C)CCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and N-(2-methoxyethyl)methylamine were converted to yield [3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-(2-methoxy-ethyl)-methyl-amine, MS: 436 (MH+, 1Br).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.Cl.[CH3:28][NH:29][CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:31]([CH2:30][N:29]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1)[CH3:28])#[N:32]
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: CNCC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN(C)CC#N)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 59 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)-phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the solution were added methylaminoacetonitrile hydrochloride (77 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 14 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[N-(cyanomethyl)-N-methylaminomethyl]phenyl]-3-(4-methylphenyl)-cinnamamide (Compound 64) (129 mg) as colorless crystals.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[OH:23][C:7]1[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])=[N:11][CH:10]=[C:9]2[N:12]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:13]=[CH:14][C:8]=12
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(ccn2CCc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2c(ccn2CCc2ccccc2)c1O

Procedure:
Prepared in analogy to that of Example 1(e) from 4-hydroxy-1-phenethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 340 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.009 mL (0.080 mMol) 4-fluorobenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:39][CH3:40])=[C:5]([CH:36]=[CH:37][CH:38]=1)[C:6]([O:19][CH2:20][C@H:21]1[O:25][C@@H:24]([N:26]2[CH:33]=[CH:32][C:30](=O)[NH:29][C:27]2=[O:28])[C@H:23]([OH:34])[C@@H:22]1[OH:35])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:41]1[CH:45]=[N:44][CH:43]=[N:42]1>>[CH3:1][O:2][C:3]1[C:4]([O:39][CH3:40])=[C:5]([CH:36]=[CH:37][CH:38]=1)[C:6]([O:19][CH2:20][C@H:21]1[O:25][C@@H:24]([N:26]2[CH:33]=[CH:32][C:30]([N:41]3[CH:45]=[N:44][CH:43]=[N:42]3)=[N:29][C:27]2=[O:28])[C@H:23]([OH:34])[C@@H:22]1[OH:35])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1nc[nH]n1
Reactant: COc1cccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccccc2)c1OC
Product: COc1cccc(C(OC[C@H]2O[C@@H](n3ccc(-n4cncn4)nc3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccccc2)c1OC

Procedure:
The method in which 5′-O-(dimethoxytrityl)uridine derivatives are condensed with 1,2,4-triazole to give 1-[5′-O-(dimethoxytrityl)-β-D-ribofuranosyl]-4-(1,2,4-tri azol-1-yl)pyrimidin-2-(1H) -one derivatives, which are then reacted with an amine in dioxane solvent to yield 5′-O-(dimethoxytrityl)cytidine derivatives (Journal of Organic Chemistry, 47, 3623 (1982)).