Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH3:17])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>ClCCl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH3:17])(=[O:28])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
4-Chloro-4'-methylsulfinylmethylbenzophenone (2.9 g) and m-chloroperbenzoic acid (2.5 g) were dissolved in dichloromethane, and the mixture was stirred for 12 hours at 0° C. After the precipitated crystals were filtered off, the filtrate was successively washed with aquous sodium bicarbonate solution, aqueous 5% sodium thiosulfate solution and water, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:5) to obtain 4-chloro-4'-methylsulfonylmethylbenzophenone (1.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH2:14][CH2:15][N:16]=[C:17]([CH3:18])[C:12]3=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>CO.O.C(O)C>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH2:14][CH2:15][NH:16][CH:17]([CH3:18])[C:12]3=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc3n2CCN=C3C)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccc3n2CCNC3C)cc1
Yield: 47 %

Procedure:
3,4-Dihydro-6-(p-methoxyphenyl)-1-methylpyrrolo[1,2-a]pyrazine (1.0 g) was dissolved in a mixture of 60 ml of methanol and 6 ml of water under argon. The solution was treated portionwise with 0.5 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 100 ml of methylene chloride and washed with 45 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 50 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 1.0 g of brown solid, was dissolved in a 30-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.7 g (47%) of 1,2,3,4-tetrahydro-6-(p-methoxyphenyl)-1-methylpyrrolo[1,2-a]pyrazine fumarate (1:0.9); m.pt.: 162°-165° C. (dec.).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([O:11]CC)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].Cl>CS(C)=O>[F:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1ncc(Cl)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ncc(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
70 g of ethyl 3-fluoro-5-chloro-2-pyridinecarboxylate (Example H1) are initially introduced into 105 ml of dimethyl sulfoxide (DMSO). 230 ml of a 2N sodium hydroxide solution are added dropwise at 40° C. in the course of 30 minutes. The resulting yellow suspension is introduced into a mixture of 2 l of ice-water and 400 ml of 2N hydrochloric acid. After subsequently stirring for 20 minutes, the mixture is filtered and the material on the filter is washed twice with water. 56.4 g of the desired target compound are obtained as a white solid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1)([O-:5])=[O:4].[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>CCOCC.O1CCCC1.C(O)C>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[CH:11][C:12](=[O:14])[CH2:13][C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:16]=1)([O-:5])=[O:4]
Reactant: CC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
Ethanol (9.5 ml) is added to a suspension of 60% sodium hydride (26.3 g) in anhydrous ether (750 ml), and thereto is added dropwise a mixture of p-nitrobenzalacetone (130 g), diethyl oxalate (99.4 g) and anhydrous tetrahydrofuran (550 ml) at 5°-10° C. with agitation. The mixture is agitated at room temperature for one hour, and thereto is added 10% hydrochloric acid (350 ml). The precipitated yellow solid is collected by filtration, washed with ether and then recrystallized from acetone to give ethyl 6-(4-nitrophenyl)-2,4-dioxo-hex-5-enoate (87.8 g). M.P. 148.5°-153.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:16])=[C:4]([NH2:15])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:17](OCC)(OCC)OCC>>[Br:1][C:2]1[C:3]2[NH:16][CH:17]=[N:15][C:4]=2[C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: CN1CCN(c2ncc(Br)c(N)c2N)CC1
Product: CN1CCN(c2ncc(Br)c3[nH]cnc23)CC1
Temperature: 130 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A 100 mL round bottom flask was charged with 5-bromo-2-(4-methylpiperazin-1-yl)pyridine-3,4-diamine (1.1 g, 3.8 mmol) and triethyl orthoformate (20 mL). The resulting mixture was stirred at 130° C. for 1 h. Reaction progress was monitored by TLC (EtOAc/petroleum ether=2:1). Work-up: the reaction mixture was concentrated in vacuo. The residue was re-dissolved in EtOAc (50 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 10-40% EtOAc in CH2Cl2, to afford 0.9 g (79%) of the product as a white solid. MS m/z: 296 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH2:24][OH:25])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:31][C:32](=[O:42])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37](O)[CH:36]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[CH2:24][O:25][C:39]1[CH:40]=[C:35]([CH2:34][CH2:33][C:32]([OH:42])=[O:31])[CH:36]=[CH:37][CH:38]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:27])[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)CCc1cccc(O)c1
Product: O=C(O)CCc1cccc(OCc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from [3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenyl]-methanol and 3-(3-hydroxy-phenyl)-propionic acid methyl ester according to the procedure of Example 69. MS (ESI) m/z 542.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:12]=[C:11]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:10]=[C:9]([Cl:20])[N:8]=1)(=O)=O.[CH:21]1([CH2:24]O)[CH2:23][CH2:22]1.[OH-].[Na+].C(=O)=O>C1C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O.O>[Cl:20][C:9]1[N:8]=[C:7]([CH2:6][O:5][CH2:24][CH:21]2[CH2:23][CH2:22]2)[CH:12]=[C:11]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:10]=1
Reactant: CS(=O)(=O)OCc1cc(COCC(F)(F)F)nc(Cl)n1
Reactant: OCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C=O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: c1ccccc1
Product: FC(F)(F)COCc1cc(COCC2CC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2-Chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)methyl methanesulfonate (0.47 g, 1.40 mmol) was dissolved in benzene (8 mL). Cyclopropylmethanol (0.222 mL, 2.81 mmol), 5 M sodium hydroxide (0.421 mL, 2.11 mmol) and tetrabutylammonium hydrogen sulfate (48 mg, 0.14 mmol) were added. The mixture was stirred vigorously at ambient temperature for 3 h. Solid carbon dioxide was added followed by brine and water. The mixture was extracted twice with ethyl acetate, the organic phase was separated and dried over sodium sulfate. The solution was concentrated in vacuum, and the residue was purified by column chromatography on silica eluting with a gradient of 0-50% of ethyl acetate in heptane. The solvents were evaporated and the residue was purified by preparative HPLC to give the title compound, 33 mg (7.5%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]1[C:6](=[CH:7][C:8](=[O:34])[C:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:10]1)[O:5]2.CC1C=C(C)N=C(C)C=1.[CH3:44][C:45]([O:47][CH2:48][CH:49]1[O:54][C@H:53](Br)[CH:52]([O:56][C:57]([CH3:59])=[O:58])[C@@H:51]([O:60][C:61]([CH3:63])=[O:62])[C@H:50]1[O:64][C:65]([CH3:67])=[O:66])=[O:46]>ClCCl.C(=O)([O-])[O-].[Ag+2]>[CH2:16]([C:9]1[C:8](=[O:34])[CH:7]=[C:6]2[C:11](=[N:12][C:13]3[C:4]([O:5]2)=[CH:3][C:2]([O:1][C@@H:53]2[O:54][C@H:49]([CH2:48][O:47][C:45](=[O:46])[CH3:44])[C@H:50]([O:64][C:65](=[O:66])[CH3:67])[C@H:51]([O:60][C:61](=[O:62])[CH3:63])[C@H:52]2[O:56][C:57](=[O:58])[CH3:59])=[CH:15][CH:14]=3)[CH:10]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCCc1cc2nc3ccc(O)cc3oc-2cc1=O
Reactant: CC(=O)OCC1O[C@H](Br)C(OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCCCCCCCCCCCCCCCCCc1cc2nc3ccc(O[C@@H]4O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)cc3oc-2cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-hydroxy-2-octadecyl-3H-phenoxazine-3-one ("octadecylresorufin) (220 mg, 0.47 mmole), powdered, activated 4Å molecular sieves (0.5 g), sym-collidine (125 μL, 0.95 mmole), and silver carbonate (155 mg, 0.56 mmole) in dry dichloromethane (20 mL) is allowed to stir at room temperature, under an atmosphere of dry nitrogen gas, in the dark for 1 hour. To this mixture is added 1-bromo-2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside (389 mg, 0.95 mmole), slowly with stirring, and the resulting heterogenous solution allowed to stir as above for 72 hours. After this time the reaction mixture is filtered through a pad of diatomaceous earth. The precipitate is washed with chloroform (5×10 mL) and the combined organic filtrates are extracted with 1M aqueous HCl (1×75 mL), saturated aqueous sodium bicarbonate solution (1×75 mL), 1M sodium thiosulfate (1×75 mL), and water (1×75 mL). The organic layer is dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure, and dried in vacuo to an orange-brown powder (440 mg). An analytical sample of the title compound can be isolated by preparative t.l.c. (20×20 cm SiO2 plate; eluent=9:1 chloroform:ethylacetate) with the bright-orange product eluting at the highest Rf (0.44), (50 mg from 200 mg applied).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[CH:14]=[C:13]([NH2:18])[N:12]=1.[N:19]([O-])=[O:20].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:12]=[C:13]([NH2:18])[C:14]([N:19]=[O:20])=[C:15]([NH2:17])[N:16]=1
Reactant: Nc1cc(N)nc(SCc2cccc(F)c2F)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N=O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 153.7 %

Procedure:
The product of step (a) (2.5 g) was dissolved in acetic acid (150 ml) and the solution cooled to 5° C. A solution of sodium nitrite (625 mg) in water (50 ml) was added dropwise resulting in a dark blue colouration. The reaction was stirred at room temperature for 30 minutes during which time a pink solid precipitated from solution. This was isolated by filtration and washed with water, then dried at 50° C. to give the sub-titled product as a blue solid (4.14 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15](OCC)=[O:16])[C:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:7]2)([O-:3])=[O:2].C1COCC1.O.Cl>CCO>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][OH:16])[C:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)CCn1c(-c2ccccc2)cc2cc([N+](=O)[O-])ccc21
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)cc(-c1ccccc1)n2CCCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
To a solution containing ethyl 3-(5-nitro-2-phenyl-1H-indol-1-yl)propanoate (prepared as described in example 1g) (2.1 g; 6.2 mmol) in THF (20 ml) sodium borohydride (0.98 g, 24.8 mmol) and EtOH absolute (25 ml) were added; the reaction mixture was left under stirring at room temperature for 18 hours. Then water (5 ml) and HCl 2N were added to pH 6. The solution was transferred into a separating funnel, and extracted with ethyl acetate (2×50 ml). The organic phases were combined, and dried over Na2SO4. The solvent was removed by evaporation under reduced pressure and the residue was purified by flash chromatography on silica gel (n-hexane/EtOAc, n-hexane 100→70%) to give 3-(5-nitro-2-phenyl-1H-indol-1-yl)propan-1-ol (1.5 g), which was used without any further purification.
Reaction SMILES: [S:1]1[C:5]([C:6]2[N:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]3=[N:8][N:7]=2)=[N:4][CH:3]=[N:2]1.Cl>>[S:1]1[C:5]([C:6]2[N:10]3[CH2:11][CH2:12][NH:13][CH2:14][C:9]3=[N:8][N:7]=2)=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nnc2-c2ncns2)C1
Agent: Cl
Product: c1nsc(-c2nnc3n2CCNC3)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1,1-dimethylethyl 3-(1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (I114) (51.2 mg, 0.166 mmol) in HCl (3 ml, 99 mmol) was stirred at room temp for 45 mins (a solid came out of solution). The solvents were removed and the product was passed trough an SCX cartridge (elution with 2M NH3 in MeOH) to give desired product as a white solid in 34.6 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][C@@H:33]1[CH2:38][NH:37][CH2:36][C@H:35]([CH3:39])[NH:34]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:37]5[CH2:36][C@H:35]([CH3:39])[NH:34][C@H:33]([CH3:32])[CH2:38]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:30])([F:31])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: C[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C[C@H](C)N1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-((3R,5S)-3,5-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R,6S) 2,6-Dimethyl-piperazine following General Procedure C.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]#[N:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][Cl:24].O>CN(C=O)C.C(OCC)(=O)C>[Cl:24][CH2:23][CH2:22][CH2:21][C:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([C:16]#[N:17])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: N#CC1c2ccccc2C=Cc2ccccc21
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC1c2ccccc2C=Cc2c(CCCCl)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5H-dibenzo[a,d]cycloheptene-5-carbonitrile (described in J. Med Chem. 1994, 37, 804-810) (500mg) in DMF (10 ml) were added 60% sodium hydride (110 mg) and 1-bromo-3- chloropropane (0.30 ml) and the mixture was stirred at room temperature for 1 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 5-(3-chloropropyl-5H-dibenzo[a,d]cycloheptene-5-carbonitrile. Without purification, to a solution obtained chloride in DMF (10 ml) were added 4-(4-chlorophenyl)-4- hydroxypiperidine (650 mg), potassium carbonate (950 mg), and potassium iodide (50 mg) and the mixture was stirred at 70° C. for 24 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to give the titled compound (700 mg). 1H-NMR (CDCl3) d: 1.22-1.34(2H,m), 1.60-1.80(3H,m), 1.93-1.99(2H,m), 2.16-2.28(6H,m), 2.56-2.60(2H,m), 6.98(2H,s), 7.25-7.47(10H,m), 8.00-8.03(2H,m). MS m/z: 469(M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[O:15]1[CH2:16][CH2:17][O:18][C:19]2[CH:24]=[C:23]([C:25]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=4[O:13][CH3:14])[N:1]=3)[CH:22]=[CH:21][C:20]1=2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4c(c3)OCCO4)nc2c1
Yield: 46 %

Procedure:
2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one (120 mg, 46%) was isolated as a yellow solid. Selected data: MS (m/z): 341.03; MP 307.5-309.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH2:30][OH:31])[CH2:10][N:11]([CH3:28])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[O:26][CH3:27])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH:30]=[O:31])[CH2:10][N:11]([CH3:28])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[O:26][CH3:27])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1c(C#N)cc2ccccc2c1C(=O)N(C)C[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: COc1c(C#N)cc2ccccc2c1C(=O)N(C)C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1

Procedure:
The alcohol from (g) was oxidized using oxalyl chloride and DMSO under standard Swern conditions to afford the aldehyde. 1H NMR (300 MHz, DMSO-d6) δ9.70-9.64 (m), 8.67-8.57 (m), 8.07-7.97 (m), 7.80 (s), 7.72-7.55 (m), 7.52-7.48 (m), 7.40-7.33 (m), 7.12-7.10 (d), 7.04-7.02 (d), 6.87-6.83 (m), 6.37-6.29 (d), 4.53-4.44 (t), 4.11-4.00 (m), 3.94 (s), 3.92 (s), 3.91-3.73 (m), 3.71 (s), 3.45-3.38 (m), 3.33 (s), 3.14 (s), 2.97-2.95 (d), 2.63 (s), 2.60 (s); MS APCI, m/z=455 (M+). This compound was characterized as a mixture of atropoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:11][O:10][C:9]2=[O:20])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH:14]=3)[CH2:11][O:10][C:9]2=[O:20])=[CH:6][CH:7]=1
Reactant: Clc1ncccn1
Reactant: O=C1OC[C@H](c2cccc(O)c2)N1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1OC[C@H](c2cccc(Oc3ncccn3)c2)N1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To (S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)oxazolidin-2-one (0.05 mmol) is added Cs2CO3 (0.1 mmol) and 2-chloropyrimidine (0.06 mmol) in DMF (1 mL). The mixture is stirred at 80° C. for 3 h then cooled to room temperature and filtered through Whatman 0.42 μM filter and purified by preparative HPLC (C-18, 10-90% ACN/water (0.05% TFA)). HPLC-MS calculated for C19H14ClN3O3 (M+H+): 368.0, found 368.0.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3=[C:13]4[S:19][CH:18]=[CH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[C:9]2[C@H:20]([OH:22])[CH3:21])[CH2:4][CH2:3]1.[C:23](#[N:26])[CH:24]=[CH2:25].N12CCCN=C1CCCCC2>C(#N)C>[OH:22][C@@H:20]([C:9]1[N:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH2:25][CH2:24][C:23]#[N:26])[CH2:3][CH2:4]2)[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=1)[CH3:21]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCNCC1
Reactant: C=CC#N
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To a solution of (1R)-1-(1-piperidin-4-yl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)ethanol hydrochloride (21.7 mg, 0.0640 mmol) (Example 15, Step 4) in acetonitrile (0.40 mL) was added 2-propenenitrile (8.4 μL, 0.13 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (38 μL, 0.26 mmol). The resulting mixture was stirred at room temperature overnight. After evaporating to dryness, the residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (11 mg, 48%). LCMS calculated for C18H22N5OS (M+H)+: m/z=356.2. Found: 356.0.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:14][CH2:15][CH2:16][C@@H:17]2[CH2:19][C@@H:18]2[CH:20]2[CH2:25][CH2:24][N:23](C(OCC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[N:4][CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:7]=1.[H][H]>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[N:4][C:3]=1[O:14][CH2:15][CH2:16][C@@H:17]1[CH2:19][C@@H:18]1[CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: Cc1cc(N2CCNC2=O)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N2CCNC2=O)cnc1OCC[C@@H]1C[C@@H]1C1CCNCC1

Procedure:
Benzyl 4-[(1R,2S)-2-(2-{[3-methyl-5-(2-oxoimidazolidin-1-yl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carboxylate (18 mg, 0.041 mmol) in 1 mL of EtOH was treated with 10% palladium on carbon (10 mg) for 2.5 hrs under 1 atm. of hydrogen gas. The catalyst was filtered off via Gilsen 0.045 μM PTFE syringe filter and the filtrate was concentrated in vacuo to give the product used for the next reaction without further purification. LCMS (ESI) m/z 345 [M+H]+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].C(O[C:8](=[O:21])[C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C.[OH-].[Na+]>C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:14]([N:10]1[CH2:11][CH2:12][CH2:13][C@H:9]1[C:8]1([OH:21])[CH2:2][CH2:1]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC[Mg]Br
Reactant: CCOC(=O)[C@@H]1CCCN1Cc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: OC1([C@@H]2CCCN2Cc2ccccc2)CC1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
First 6.91 mL (23.57 mmol) of titanium (IV) isopropoxide and then 14.3 mL (42.9 mmol, 3 M in diethyl ether) of ethylmagnesium bromide were slowly added dropwise to a solution of 5.0 g (21.43 mmol) of N-benzyl-L-proline ethyl ester in 80 mL of dry diethyl ether which had been cooled to −15° C. and the reaction mixture was stirred for 30 minutes at this temperature. Subsequently at approximately 10° C., 5.4 mL (42.9 mmol) of boron trifluoride-diethyl ether complex were added and the mixture was stirred for a further 75 hours at RT. While cooling, 50 mL of 1M NaOH was added, the mixture was stirred for 1 hours at RT, combined with 100 mL of diethyl ether, and the organic phase was separated off and dried over sodium sulfate. After the desiccant and solvent had been eliminated, the residue was purified by chromatography (silica gel, EtOAc). Yield: 0.745 g (16% of theoretical); C14H19NO (M=217.307); calc.: molpeak (M+H)+: 218; found: molpeak (M+H)+: 218; Rf value: 0.17 (silica gel, EtOAc).