Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[O:15])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(CO)ccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc(C=O)ccn1
Reaction time: 2 h
Yield: 83 %

Procedure:
(4-Hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.91 g, 8.51 mmol) was dissolved in dry DMSO (10 mL) and the reaction flask immersed in a waterbath at 15° C. Triethylamine (1.72 g, 17.0 mmol) was added followed by sulfur trioxide pyridine complex (2.41 g, 15.1 mmol). The reaction mixture was stirred for 2 h and poured onto crushed ice and the product extracted with CHCl3. The organic extract was washed with water, dried concentrated under reduced pressure. The crude product was purified by flash chromatography (hexane/EtOAc, 80:20) to give (4-Formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.57 g, 83%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](=[O:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[CH3:1][S:2][CH2:3][C:4]([CH:5]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:6]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7])=[O:13]
Reactant: CSCC(=O)CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCC(C(=O)CSC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.3 %

Procedure:
To a solution of tert-butyl 4-(methylthio)-3-oxobutanoate (5.00 g) and potassium carbonate (3.72 g) in dimethylformamide (25 mL) was added ethyl 5-iodopentanoate (6.89 g) and the mixture was stirred at ambient temperature for 15 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-10:1) to give 1-tert-butyl 7-ethyl 2-[(methylthio)acetyl]heptanedioate as colorless oil (5.88 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]4[C:24](=O)[C:23]5=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]5[C:21]4=O)[CH2:14][CH2:13]3)=[N:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]\[C:40]([OH:42])=[O:41]>C1COCC1.CO>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]\[C:40]([OH:42])=[O:41].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]\[C:40]([OH:42])=[O:41].[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]4[CH2:24][C:23]5[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:21]4)[CH2:14][CH2:13]3)=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CO
Product: Fc1ccc2c(C3CCN(CCN4Cc5ccccc5C4)CC3)n[nH]c2c1
Temperature: 25 °C

Procedure:
To a solution of N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimide hydrochloride (Example 183) (3.1 g, 7.91 mmol) in THF (100 mi) was added lithium aluminum hydride (16.6 ml of a 1.0M solution in THF, 16.6 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux for 6.5 hours and cooled to room temperature. The reaction was quenched with water (1.5 ml, dropwise) and the precipitated salts were removed via filtration. The solids were washed with DCM and the combined filtrates concentrated to give 2.5 g of the crude product as a solid. The dimaleate salt was prepared in methanol using 3.5 g (>4.0 e.q.) of maleic acid. The light green precipitate was collected via filtration and washed with methanol. Recrystallization from methanol gave 2.1 g of the desired product as an off-white solid, m.p. 196°-199° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][N:49]([CH3:51])[CH3:50])=[CH:42][CH:41]=1>C(O)C>[CH3:50][N:49]([CH3:51])[CH2:48][CH2:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:7]2[N:8]=[CH:9][C:10]3=[C:2]([CH3:1])[N:3]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:5]3[N:6]=2)=[CH:41][CH:42]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: Cc1nc(-c2ccccc2)n2nc(Nc3ccc(OCCN(C)C)cc3)ncc12
Yield: 24.2 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), {2-[(4-aminophenyl)oxy]ethyl}dimethylamine (32 mg, 0.17 mmol) and ethanol (2.5 mL) to afford N-(4-{[2-(dimethylamino)ethyl]oxy}-phenyl)-5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (16 mg) as a yellow solid. MS m/z 389 (M+1).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:34]=[CH:33][C:9]([CH:10]([C:23]([OH:32])([CH2:28][C:29]([CH3:31])=[CH2:30])[C:24]([F:27])([F:26])[F:25])[NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[N:15][C:16]([CH3:22])=[N:17]3)=[C:8]([O:35][CH3:36])[CH:7]=1>CCCCCC.C(OCC)(=O)C>[F:5][C:6]1[CH:34]=[CH:33][C:9]([CH:10]([C:23]([OH:32])([CH:28]=[C:29]([CH3:30])[CH3:31])[C:24]([F:26])([F:25])[F:27])[NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[N:15][C:16]([CH3:22])=[N:17]3)=[C:8]([O:35][CH3:36])[CH:7]=1
Reactant: C=C(C)CC(O)(C(Nc1cccc2nc(C)ncc12)c1ccc(F)cc1OC)C(F)(F)F
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(F)ccc1C(Nc1cccc2nc(C)ncc12)C(O)(C=C(C)C)C(F)(F)F

Procedure:
Analogously to Example 6, 340 mg (1.1 mmol) of 4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 211 mg (1.32 mmol) of 5-amino-2-methylquinazoline (described in Example 6) are reacted with 0.46 ml (2.2 mmol) of titanium tetraethylate to form imine. After analogous rearrangement with boron tribromide and subsequent chromatography on silica gel with hexane-ethyl acetate (0-50%), 156 mg of a mixture that consists of 2-{4-fluoro-alpha-[(2-methylquinazolin-5-yl)amino]-2-methoxybenzyl}-1,1,1-trifluoro-4-methylpent-4-en-2-ol and 2-{4-fluoro-alpha-[(2-methylquinazolin-5-yl)amino]-2-methoxybenzyl}-1,1,1-trifluoro-4-methylpent-3-en-2-ol is obtained. The separation is carried out by means of preparative thin-layer chromatography on silica gel (dichloromethane/2-propanol 5%) and yields 51 mg of the main component and 9 mg of the minor component.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28](O)=[O:29])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28]([N:32]([CH3:33])[CH3:31])=[O:29])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:17][C:16]3=[O:27])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(Nc1ccc(F)cc1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNC
Product: CC(Nc1ccc(F)cc1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 60.3 %

Procedure:
8-(1-(4-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (82 mg, 0.20 mmol) was reacted with dimethylamine (0.119 mL, 0.24 mmol) using a procedure similar to the one described in Example 2.00 to afford 8-(1-(4-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (53 mg, 60.7%) as a white solid. Mass Spectrum: M+H+ 440. NMR Spectrum: (DMSOd6) 1.50 (d, 3H), 2.66 (s, 3H), 2.92 (s, 3H), 3.50-3.65 (m, 4H), 3.70-3.81 (m, 4H), 4.92-5.02 (m, 1H), 5.60 (s, 1H), 6.27 (d, 1H), 6.46 (dd, 2H), 6.84 (dd, 2H), 7.56 (d, 1H), 7.77 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][F:16])[CH:8]=[CH:7][N:6]=1)=[O:4].Cl>CO.O.[Pt]=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][F:16])[CH2:8][CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)c1cc(CCCCCF)ccn1
Agent: O=[Pt]
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)C1CC(CCCCCF)CCN1
Reaction time: 8 h

Procedure:
To a mixture of 4-(5-fluoro-pentyl)-pyridine-2-carboxylic acid methyl ester (254 mg, 1.13 mmol) in MeOH (5 mL) and water (5 mL) were added conc. HCl (0.28 mL, 3.39 mmol, 3 equiv) and platinum oxide (130 mg). The mixture was purged and charged with hydrogen (1 atm) and stirred overnight. The platinum oxide was removed by filtration and the filtrate was evaporated to give 4-(5-fluoro-pentyl)-piperidine-2-carboxylic acid 2-methyl ester.
Reaction SMILES: [CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][C:29]([O:31]CC)=[O:30])[C:20]3=[O:34])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[OH-].[Na+].O.Cl>C(O)C>[CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][C:29]([OH:31])=[O:30])[C:20]3=[O:34])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CCOC(=O)Cn1c(=O)n(C2CCN(C3Cc4cccc5cccc3c45)CC2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1c(=O)n(C2CCN(C3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
Ethyl (RS)-2-{3-[1-(acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzoimidazol-1-yl}acetate (1.6 g) was dissolved in ethanol (10 ml) and 2N-aqueous sodium hydroxide solution (10 ml) was added. The mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water, thereto was added to 1N-hydrochloric acid for neutralization, and the mixture was extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained solid was washed with ethyl acetate to give the title compound (1.3 g) as pale-yellow crystals.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:7]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]2)=[O:9])=[C:6]([O:26][CH2:27][CH2:28][O:29][CH3:30])[N:5]=1>C1COCC1.O>[CH3:30][O:29][CH2:28][CH2:27][O:26][C:6]1[N:5]=[C:4]([NH:2][CH3:1])[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:7]=1[C:8]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]1)=[O:9]
Reactant: COCCOc1nc(Cl)c([N+](=O)[O-])cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(OCCOC)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]

Procedure:
Methylamine (2 M in THF; 400 μL, 0.80 mmol) is added to 6-chloro-2-(2-methoxy-ethoxy)-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (150 mg, 0.35 mmol) in THF (10 mL). After 45 min at rt the reaction mixture is diluted with water, concentrated and filtered. The filtercake is washed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([OH:25])[C:9]=3[C:8]2=[O:26])=[CH:4][CH:3]=1.[N+](=[CH2:31])=[N-]>ClCCl.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:25][CH3:31])[C:9]=3[C:8]2=[O:26])=[CH:27][CH:28]=1
Reactant: C=[N+]=[N-]
Reactant: COCOc1c2c(c(O)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Solvent: ClCCl
Solvent: CCOCC
Product: COCOc1c2c(c(OC)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reaction time: 0.33 h

Procedure:
Methoxymethyl ether 6 (0.02 g, 0.052 mmol) was dissolved in 2 mL dry dichloromethane at 0° C. An excess of a diazomethane solution in diethylether was added. After about 20 minutes, all starting 6 was consumed. The mixture was concentrated in vacuo to give crude 7-(4-fluoro-benzyl)-5-methoxy-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,8-dione 8 (0.0223 g, 0.0527 mmol). 1H NMR (CDCl3) δ 9.1 (dd, 1H), 8.7 (dd, 1H), 7.6 (dd, 1H), 7.5 (t, 2H), 7.0 (t, 2H), 5.8 (s, 2 H), 4.8 (s, 2 H), 4.4 (s, 3H), 3.7 (s, (s, 3H), MS: 397 (M+1); 419 (M+23).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].OCCS(C1C(OCCC)=C(OC)C=C([C@@H:19]([OH:36])[CH2:20][CH2:21][CH:22]([C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)O)C=1)(=O)=O.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(Cl)(Cl)Cl>[CH3:31][O:30][C:28]1[CH:29]=[C:24]([CH:22]2[O:36][CH2:19][CH2:20][CH2:21]2)[CH:25]=[C:26]([O:34][CH3:35])[C:27]=1[O:32][CH3:33]
Reactant: CCCOc1c(OC)cc([C@@H](O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cc(C2CCCO2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of the more mobile fraction of 1-(5-(2-hydroxyethylsulfonyl)-4-n-propoxy-3-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl-4-oxo-butan-1-yl(R)-(O)-methylmandelate (200 mg, 0.300 mmole) in dry THF (15 mL) at 0° C. under nitrogen atmosphere was treated with lithium aluminum hydride (20 mg, 0.5 mmole), and stirred for 2 hours. After the usual workup, the crude (1S, 4RS)-1-(5-(2-hydroxyethylsulfonyl)-4-n-propoxy-3-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-butan-1,4-diol was dissolved in chloroform (2 mL, stabilized with ethanol), chilled to 0° C., stirred, and treated with 10% (v/v) of trifluoroacetic acid in chloroform (2 mL, stabilized with ethanol). After 4 hours at 0° C., anhydrous Na2CO3 (1.0 mg, 9.4 mmole) was added, and the mixture was stirred for additional 15 minutes. The mixture was then filtered, and the filtrate was evaporated to a syrup which was purified by preparative TLC SiO2 plates developed with 3:2 (v/v) ethyl acetate hexane to provide (-)-(2S,5S)-2-(5-2-hydroxyethylsulfonyl)-4-n-propoxy-3-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran, m.p. 111°-112° C.; [α]D -61.4° (c=1, CHCl3).
Reaction SMILES: C1C2C(COC([N:18]=[C:19]=[S:20])=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.[CH2:22]([O:24][C:25](=[O:35])[C:26]([CH3:34])([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27])[CH3:23].C(=O)([O-])O.[Na+].N1CCCCC1>C(Cl)(Cl)Cl.C(OCC)C>[CH2:22]([O:24][C:25](=[O:35])[C:26]([CH3:34])([CH:28]1[CH2:33][CH2:32][N:31]([C:19](=[S:20])[NH2:18])[CH2:30][CH2:29]1)[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)C1CCNCC1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)(C)C1CCN(C(N)=S)CC1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of 9-fluorenylmethoxycarbonylisothiocyanate (2.62 g, 9.32 mmol) in chloroform (20 ml), a solution of 2-methyl-2-piperidin-4-yl-propionic acid ethyl ester hydrochloride (2.27 g, 9.61 mmol) in chloroform (10 ml) and sodium hydrogen carbonate (4.03 g, 48.0 mmol) were added and the mixture was stirred at room temperature. Further, piperidine (30 ml) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo, and the solid obtained by adding diethyl ether was collected by filtration. The solid was dissolved in N,N-dimethylformamide (20 ml) and piperidine (20 ml) was added and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated brine and dried over sodium sulfate, and the residue obtained by vacuum concentration was purified by silica gel chromatography (n-hexane:ethyl acetate) and the title compound (2.4 g, 98%) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19]COC)[C:12](=[O:18])[N:13](COC)[CH:14]=2)=[CH:5][CH:4]=1)[CH3:2].Cl>O1CCOCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([OH:19])[C:12](=[O:18])[NH:13][CH:14]=2)=[CH:23][CH:24]=1)[CH3:2]
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1ccc(CSc2c[nH]c(=O)c(O)c2)cc1
Yield: 23.5 %

Procedure:
A solution of 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)-pyridin-2(1H)-one (253 mg, 0.724 mmol) (Intermediate 17) in hydrogen chloride solution (4 M in dioxane; 2.10 ml, 8.50 mmol) and dioxane (2 ml) was heated under reflux overnight. The reaction mixture was concentrated in vacuo and the resulting solid was recrystallised in boiling ethanol/water. The resulting recrystallised solid was filtered and dried to yield 5-[(4-ethylbenzyl)sulfanyl]-3-hydroxypyridin-2(1H)-one (45 mg, 0.17 mmol, 20% yield).
Reaction SMILES: I[C:2]1[CH:19]=[N:18][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=O)[C:4]=2[CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:24])[C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:19]=[N:18][C:5]3[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:4]=3[CH:3]=2)=[CH:27][CH:26]=1)[CH3:21]
Reactant: O=C(c1ccccc1)N1CCNc2ncc(I)cc21
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)CCN3)cc1
Yield: 42 %

Procedure:
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenyl-methanone (293 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A to give the title compound as a pale yellow solid (42% yield). M.p. 178-179° C., LCMS: m/z=374.30 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.38 (t, J=7.1) Hz, 3H), 3.40 (t, J=5.1 Hz, 2H), 3.60-3.63 (m, 2H), 4.35 (q, J=7.1 Hz, 2H), 4.48 (s, 2H), 6.85 (s, 1H), 7.27-7.49 (m, 5H), 7.43 (d, J=8.3 Hz, 2H), 7.73 (d, J=2.0 Hz, 2H), 8.00 (d, J=8.3 Hz, 2H).
Reaction SMILES: [C:1]1([CH-:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].[CH3:15][C:16]([CH3:22])=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>C1COCC1>[CH:17]1([C:16]([CH3:22])([CH3:15])[CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:21]=[CH:20][CH:19]=[CH:18]1
Reactant: CC(C)=C1C=CC=C1
Reactant: c1ccc([CH-]c2ccccc2)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C1C=CC=C1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium diphenylmethanide (5.72 g, 27.8 mmols) in about 50 mL of THF was slowly added to 6,6-dimethylfulvene (2.94 g, 27.8 mmols) in about 100 mL of THF at about 25 C. The reaction mixture was stirred at about 25° C. for about 16 hours. The solvent was removed under reduced pressure to give the desired product as a sticky, oily solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[NH:12][C:13]([CH2:15][CH3:16])=[N:14][C:6]1=[N:5]2.[Cl:17][C:18]([SH:21])([Cl:20])[Cl:19].O1CCCC1.C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[N:12]([S:21][C:18]([Cl:20])([Cl:19])[Cl:17])[C:13]([CH2:15][CH3:16])=[N:14][C:6]1=[N:5]2
Reactant: SC(Cl)(Cl)Cl
Reactant: CCc1nc2nc3cc(Cl)ccc3nc2[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1nc2nc3cc(Cl)ccc3nc2n1SC(Cl)(Cl)Cl

Procedure:
Two parts of 6-chloro-2-ethyl-1H-imidazo[4,5-b]quinoxaline was combined with two parts of perchloromethyl mercaptan in sixty parts of tetrahydrofuran. One part of triethylamine was added slowly dropwise at 30° over a one-hour period. The mixture was poured into water and crude product was collected. The material was recrystallized from a chloroform:hexane mixture to give 1 part of 6-chloro-2-ethyl-1-trichloromethanesulfenyl-1H-imidazo[4,5-b]quinoxaline, m.p. 250° (dec.).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=4[N:19](C(C)=C)[C:18]3=[O:30])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Cl.C(O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:30])[CH2:10][CH2:9]2)=[O:7])=[CH:31][CH:32]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cc(C)ccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2[nH]c(=O)n(CCCN3CCC(C(=O)c4ccc(F)cc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
A mixture of 4.5 parts of 3-{3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-1-(1-methylethenyl)-2H-benzimidazol-2one, 24 parts of a concentrated hydrochloric acid solution, 80 parts of ethanol and 50 parts of water is stirred for 2 hours at room temperature. The reaction mixture is evaporated and the residue is stirred in water. The whole is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 1 part (25%) of 1-{3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl}-1,3-dihydro-6-methyl-2H-benzimidazol-2-one; mp. 149.7° C
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]=2[N:6]=1.Cl.Cl.[CH3:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([N:28]2[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]2)[CH:23]=1.CCN(C(C)C)C(C)C.CN1CCCC1=O>O1CCOCC1.O>[CH3:12][O:11][C:10]1[C:4]2[S:3][C:2]([NH:34][CH:31]3[CH2:32][CH2:33][N:28]([C:24]4[CH:23]=[C:22]([CH3:21])[N:27]=[CH:26][N:25]=4)[CH2:29][CH2:30]3)=[N:6][C:5]=2[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=1
Reactant: Cc1cc(N2CCC(N)CC2)ncn1
Reactant: COc1ccc(-c2ccccc2)c2nc(Cl)sc12
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccccc2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)sc12
Temperature: 200 °C
Yield: 25.5 %

Procedure:
A solution of 2-chloro-7-methoxy-4-phenylbenzo[d]thiazole (100 mg, 363 μmol), 1-(6-methylpyrimidin-4-yl)piperidin-4-amine dihydrochloride (115 mg, 435 μmol) and Hunig's base (187 mg, 253 μL, 1.45 mmol) in dioxane (2 mL) was heated to 160° C. in a microwave oven for 30 minutes. N-Methyl-2-pyrrolidinone (0.5 mL) was added and the reaction was heated to 200° C. in a microwave oven for 2 hours. Water was added and the reaction was extracted twice with dichloromethane. The combined organic layers were washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel using a gradient from dichloromethane to dichloromethane/methanol 9:1 (v/v) as eluent to yield the title compound as a light brown solid (40 mg, 25%). MS ISP (m/e): 432.4 (100) [(M+H)+].