Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:15]([CH:16](O)[C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][C:13]2[C:12]([CH3:24])([CH3:23])[CH2:11][CH2:10][C:9]([CH3:26])([CH3:25])[C:8]=2[CH:7]=1>C(OCC)(=O)C.[Pd]>[CH:2]([C:6]1[C:15]([CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][C:13]2[C:12]([CH3:24])([CH3:23])[CH2:11][CH2:10][C:9]([CH3:26])([CH3:25])[C:8]=2[CH:7]=1)=[O:1]
Reactant: CC1(C)CCC(C)(C)c2cc(C(O)c3cccs3)c(C3OCCO3)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(Cc3cccs3)c(C=O)cc21
Reaction time: 4 h
Yield: 62 %

Procedure:
The alcohol prepared above was dissolved in 7 mL of ethyl acetate and 75 mg of 10% Pd/C was added and the reaction mixture stirred under a hydrogen atmosphere for about 4 hours. The reaction mixture was filtered through Celite and concentrated in vacuo. The resulting residue was purified by preparative thin layer chromatography (10% ethyl acetate/hexane) to give 2-formyl-3-[(thiophene-2-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (94 mg, 62%) directly.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH2:19]C)=[O:17])[CH:10]=1.BrCCBr>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:19][O:18][C:16]([C:15]1([C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1)=[O:17]
Reactant: CCOC(=O)Cc1cccnc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: BrCCBr
Product: COC(=O)C1(c2cccnc2)CC1
Temperature: -78 °C
Reaction time: 0.83 h

Procedure:
To a cooled (−78° C.) solution of LDA (2.0M, 272 mL) in 500 mL anhydrous THF and 200 ml HMPA (dried with molecular sieves) was added gradually a solution of ethyl 3-pyridylacetate 7-1 (75.0 g, 454 mmol) in 50 mL THF. The mixture was stirred for 50 min at −78° C. and treated with neat 1,2-dibromoethane (117 mL, 1363 mmol) in one portion. The reaction mixture was stirred overnight while being allowed to warm to room temperature. The reaction mixture was quenched with saturated NH4Cl and extracted three times with EtOAc. The combined organic layers were washed three times with H2O and then brine. After solvent removal, the residue was purified using silica gel chromatography (100% hexanes to EtOAc/hexane=7/3) to obtain the desired product 7-2 as an oil.
Reaction SMILES: NCC(O)CO.Cl.[C:8]([CH:11]([N:18]1[CH2:29][CH2:28][N:27]([CH:30]([C:37]([OH:39])=[O:38])CCCC(O)=O)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][N:21]([CH:40](CCCC)[C:41]([OH:43])=[O:42])[CH2:20][CH2:19]1)CCCC(O)=O)([OH:10])=[O:9].C1C(=O)N(O)C(=O)C1S([O-])(=O)=O.[Na+].CCN=C=NCCCN(C)C.[OH-].[Na+]>O>[CH2:25]1[NH:24][CH2:23][CH2:22][N:21]([CH2:40][C:41]([OH:43])=[O:42])[CH2:20][CH2:19][N:18]([CH2:11][C:8]([OH:10])=[O:9])[CH2:29][CH2:28][N:27]([CH2:30][C:37]([OH:39])=[O:38])[CH2:26]1
Reactant: CCCCC(C(=O)O)N1CCNCCN(C(CCCC(=O)O)C(=O)O)CCN(C(CCCC(=O)O)C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NCC(O)CO
Solvent: O
Product: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reaction time: 8 h

Procedure:
A solution containing 0.26 mg of 3-aminopropane-1,2-diol in 6 μl of water is prepared. The pH is adjusted to 6 with HCl. 0.5 mg of gallium complex of 2-[4,7-bis(1,4-dicarboxybutyl]-1,4,7,10-tetraazacyclododec-1-yl]hexanoic acid are added to the above solution. The pH is again adjusted before adding 0.071 mg of sulfo-NHS and 0.062 mg of EDCI. The pH is checked and adjusted to 6 with 2N NaOH. After an overnight period at AT, the reaction medium is concentrated to approximately 2 ml and then precipitated from 10 ml of ethanol. The solid is filtered off, washed with ethanol and diethyl ether, and then purified on silanized silica RP2, elution being carried out with water only. 0.2 mg of product is obtained.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][N:4]2[C:3]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[N:2]1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+].[NH4+]>CCOCC>[C:12]1([C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:3]2[N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]3[CH2:1][N:2]=2)[OH:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(C1=NCC2CCCCN12)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(C1=NCC2CCCCN12)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The oil from Example 2 was dissolved in dried ether (25 ml.) and immediately added to phenylmagnesium bromide (prepared from 1.23g. magnesium and 8.00g. bromobenzene) in 150ml. dried ether. The mixture was stirred at room temperature for 16 hours. It was then poured on to a mixture of ammonium chloride (2.7g.) and ice and basified with ammonium solution. The solid remaining in the mixture was removed by filtration, and the ether layer was combined with chloroform extracts of the aqueous layer, dried over magnesium sulphate and evaporated to a residue. This residue and that from chloroform washings of the solid remaining after the Grignard reaction was crystallised from ethanol to give the title compound (0.56g.), m.p. 131°-3°C.
Reaction SMILES: [C:1]1([CH2:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18](Cl)[N:17]=1>C1COCC1>[NH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([O:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:17]=1
Reactant: Nc1cc(Cl)nc(Cl)n1
Reactant: OCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cc(Cl)nc(OCc2cccc3ccccc23)n1
Reaction time: 0.5 h

Procedure:
1-Naphthalenemethanol (227 mg, 1.44 mmol) is added to a slurry of 50% sodium hydride (69 mg, 1.44 mmol) in dry THF (4 ml) at 0° C. After stirring for 30 minutes, 4-amino-2,6-dichloropyrimidine (157 mg, 0.96 mmol) is added and stirred at 22° C. for 72 hours. The solution is quenched with saturated NH4Cl and concentrated in vacuo. The residue is dissolved in methylene chloride and washed 3× saturated NaHCO3, dried with MgSO4, filtered, and concentrated in vacuo. The sample is purified by chromatography using 1:2 ethyl acetate/hexanes and recrystallization from heptane/toluene, mp 160-161° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>COCCOC>[Cl:1][C:2]1[C:7]2[CH:8]=[N:12][NH:13][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1c(Cl)ccnc1Cl
Reactant: NN
Solvent: O
Solvent: COCCOC
Product: Clc1nccc2[nH]ncc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of 2,4-dichloropyridine-3-carbaldehyde (7.0 g) in DME (70 mL) was added hydrazine monohydrate (8.0 g) at room temperature. The reaction mixture was stirred overnight at 75° C., and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (4.0 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[Br:12]N1C(=O)CCC1=O>ClCCl>[Br:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH2:3][C:4]2=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCNc2ccccc21
Solvent: ClCCl
Product: O=C1CCNc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
To a solution of 2,3-dihydroquinolin-4(1H)-one (2.94 g) in dichloromethane (25 mL) was added N-bromosuccinimide (3.63 g). The mixture was stirred at room temperature for 1.5 h and was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated. The concentrate was chromatographed on silica gel using a 35% ethyl acetate in heptane solvent solution and gave 4.14 g of the title compound. MS (ESI−) for C9H8BrNO m/z 225.77 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:4][CH:3]=1.[CH3:24][C:25](=O)[CH2:26][C:27](=O)[CH3:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:24])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:4][CH:3]=1
Reactant: CC(C)Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Reactant: CC(=O)CC(C)=O
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(CC(C)C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (4-chloro-phenyl)-(2-hydrazino-9-isobutyl-9H-purin-6-yl)-amine and 2,4-pentanedione.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1([CH3:19])[C:13](=O)[NH:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[O:9]1>C1COCC1>[CH3:7][C:8]1([CH3:19])[CH2:13][NH:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[O:9]1
Reactant: CC1(C)Oc2ccccc2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CNc2ccccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a stirred solution of LAH (3.01 g, 79.10 mmol) in THF (80 mL) at 0° C. was added 2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (7.00 g, 39.5 mmol) in portions and stirred the reaction mixture at 25° C. for 1 h and then 50° C. for 3 h. Reaction mixture was quenched by the addition cold saturated sodium sulfate solution and it was filtered through celite and extracted with DCM (100 mL×2), washed with brine (50 mL), dried over sodium sulfate, concentrated to give 2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine (6.09 g), which was used as such for the next reaction without purification
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13]CC)=[O:12])=[CH:4][CH:3]=1.C[O-].[Na+].CO.O[Li].O>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CC1c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Li]O
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: O=C(O)C1CC1c1ccc(Cl)cc1
Yield: 98.5 %

Procedure:
Ethyl 2-(4-chlorophenyl)-cyclopropanecarboxylate (0.210 g, 0.935 mmol) was placed in a 50 ml flask and dissolved in EtOH (5 ml). NaOMe in MeOH (25%, 0.808 g, 3.74 mmol) was added to the mixture. The mixture was heated for 17 hours under reflux and then concentrated. The residue was dissolved in MeOH (10 ml), and 1M solution of LiOH—H2O (3.74 ml, 3.74 mmol) was added. The methanol was removed under reduced pressure. The residue was diluted with water (10 ml) and washed with EtOAc (10 ml). The aqueous layer was acidified by 1N HCl (10 ml) to pH 1 and a solid precipitated out of solution. The mixture was extracted with EtOAc (3×10 ml) and the combined extracts were dried over MgSO4, filtered, and concentrated to provide 181 mg of the title compound as a solid (98%). The crude solid was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]([C:14](O)=[O:15])[CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1>[CH3:12][CH:11]([CH3:13])[C@@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:4][CH:5]=1)[CH2:14][OH:15]
Reactant: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](CO)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
N-[4-(Trifluoromethyl)phenyl]-D-valine (2.15 g, 8.23 mmol) obtained in Step 1 of Example 1 was dissolved in tetrahydrofuran (50 ml), and triethylamine (1.71 mL, 12.3 mmol) and ethyl chloroformate (0.94 mL, 9.88 mmol) were added under cooling. The precipitated salt was filtered off, sodium borohydride (0.62 g, 16.4 mmol) and ice were added, and the mixture was stirred overnight at room temperature. The solvent was evaporated and, after work-up according to a conventional method, the residue was purified by silica gel column chromatography (30% mixed solvent of ethyl acetate/hexane) to give the title compound (0.95 g, 3.84 mmol, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Li+].Br[CH2:17][CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:21][O:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[N:7]=[CH:8][C:9]1=[O:13]
Reactant: COC(CCBr)OC
Reactant: COc1ccc2ncc(=O)[nH]c2c1
Agent: [H-]
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CCC(OC)OC)c2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.9 %

Procedure:
7-Methoxyquinoxalin-2(1H)-one (synthesized with reference to WO2009/1126; 4.13 g, 23.4 mmol) was dissolved in N,N-dimethylformamide (103 ml). The solution was cooled in an ice bath, lithium hydride (purity 90%, 248 mg, 28.1 mmol) was then added thereto and the mixture was stirred at room temperature for 40 minutes. The reaction solution was cooled in an ice bath again, 3-bromo-1,1-dimethoxypropane (3.78 ml, 28.1 mmol) and sodium iodide (4.21 g, 28.1 mmol) were added and then the mixture was stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed sequentially with saturated sodium chloride solution (×2), water and saturated sodium chloride solution, dried over magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 4.68 g (72%) of the title compound in the form of a yellow syrup.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]([CH3:31])=[C:19]([CH3:30])[C:20]4[O:24][C:23]([CH3:26])([CH3:25])[CH:22]([OH:27])[C:21]=4[C:28]=3[CH3:29])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C=O)C>[CH2:32]([O:27][CH:22]1[C:21]2[C:28]([CH3:29])=[C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=4)[CH2:16][CH2:15]3)[C:18]([CH3:31])=[C:19]([CH3:30])[C:20]=2[O:24][C:23]1([CH3:26])[CH3:25])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(OCc3ccccc3)C(C)(C)O4)CC2)cc1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Sodium hydride (60%, 0.06 g, 1.5 mmol) was added to a solution of 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol (0.30 g, 0.75 mmol) obtained in Reference Example 18 in DMF (5 ml) under ice cooling. The mixture was stirred for 30 minutes, and then benzyl bromide (0.14 g, 0.84 mmol) was added. After stirring for 30 minutes under ice cooling, the mixture was stirred for 30 minutes at room temperature. The resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 0.23 g (yield 62%) of the title compound via recrystallization (diisopropyl ether-methanol). mp. 98–99° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[C:10]([C:12]3[N:16]([CH:17]([CH3:19])[CH3:18])[N:15]=[CH:14][N:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:33]1[C:41]2[C:36](=[C:37](B3OC(C)(C)C(C)(C)O3)[C:38]([F:42])=[CH:39][CH:40]=2)[CH:35]=[CH:34]1)(C(C)(C)C)(C)C>>[F:42][C:38]1[C:37]([C:2]2[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:5]3[N:11]=[C:10]([C:12]4[N:16]([CH:17]([CH3:19])[CH3:18])[N:15]=[CH:14][N:13]=4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:36]2[C:41](=[CH:40][CH:39]=1)[NH:33][CH:34]=[CH:35]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC(C)n1ncnc1-c1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Product: CC(C)n1ncnc1-c1ccc2nc(-c3c(F)ccc4[nH]ccc34)nc(N3CCOCC3)c2n1

Procedure:
4-(2-chloro-6-(1-isopropyl-1H-1,2,4-triazol-5-yl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (0.11 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 57.7 mg of 141 following reverse phase HPLC purification. MS (Q1) 459.2 (M)+
Reaction SMILES: [C:1]1([S:7]([CH:10]=[C:11]2[CH2:14][O:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH:15]([N:28]1[CH2:33][CH2:32][N:31]([C:11]2([CH2:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH2:14][O:13][CH2:12]2)[CH2:30][CH2:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(C=C1COC1)c1ccccc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CO
Product: O=S(=O)(CC1(N2CCN(C(c3ccccc3)c3ccccc3)CC2)COC1)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 112.8 %

Procedure:
A clear solution of 3-((phenylsulfonyl)methylene)oxetane (450 mg, 1.284 mmol) in methanol (10 mL) was treated with 1-benzhydrylpiperazine (389 mg, 1.541 mmol) and stirred at 50° C. overnight, more 3-((phenylsulfonyl)methylene)oxetane (100 mg) was added, stirred at 50° C. o/n, concentrated. The crude was purified by ISCO (40 g), eluted with EA:HX=0-50%, the deired fractions were concentrated to yield 1-benzhydryl-4-(3-((phenylsulfonyl)methyl)oxetan-3-yl)piperazine (670 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[OH-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>C(O)C>[CH2:23]([O:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: Oc1ccc(O)c(Cl)c1
Reactant: CCCCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(O)cc1Cl
Yield: 16 %

Procedure:
In ethanol was dissolved 5.0 g of 4-hydroxy-3-chlorophenol, and an aqueous solution of 1.38 g of sodium hydroxide and 8.6 g of n-dodecyl bromide were added to the solution under reflux in a nitrogen atmosphere. The mixture was refluxed for 6 hours and cooled, and the thus-obtained solution was put into a 1N aqueous solution of hydrochloric acid and extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride, dehydrated on anhydrous magnesium sulfate and concentrated. The concentrate was purified by using a silica gel column to obtain 1.73 g of 4-dodecyloxy-3-chlorophenol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:37]1[C:33](=[O:43])[C:34]3[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:36]1=[O:38])=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)Cn1c(CCl)c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 95.2 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-4-(2-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone (4.27 g, 9.5 mmol) and potassium phthalimide (2.65 g, 14.3 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-[[6-benzyloxy-4-(2fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione (5.07 g, 95.3%) as an amorphous.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[C:19]([CH:21]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)[CH2:22][C:23]([O:25][CH3:26])=[O:24])#[N:20].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[C:19]([CH:21]([C:27]1[CH:32]=[CH:31][C:30]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9](=[O:10])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:17][CH:18]=2)=[CH:29][CH:28]=1)[CH2:22][C:23]([O:25][CH3:26])=[O:24])#[N:20]
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Reactant: O=C(COc1ccc(CO)cc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)CC(C#N)c1ccc(OCc2ccc(OCC(=O)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.1 %

Procedure:
To a 100 mL of two neck RB flask was charged with 2-[4-(hydroxy methyl)phenoxy]-1-phenylethanone (2.5 g, 10.3 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (2.5 g, 12.4 mmol) in 50 mL of toluene. To this added tributylphosphine (3.33 g, 16.5 mmol) at 0° C. and added 1,1′-(Azodicarbonyl)dipiperidine (4.165 g, 16.5 mmol) portion wise over a period of 15 min at 0° C. After 12 h of stirring at RT, the mixture was diluted with n-hexane and stirred for 10 min. Solid formed was filtered off and the filtrate was concentrated to afford crude product which on trituration with ethyl acetate and pet ether gave pure product. (2.5 g yield: 56.1%); 1H NMR (300 MHz, DMSO-d6): δ 8.01-8.03 (d, 2H), 7.67-7.72 (t, 1H), 7.55-7.60 (t, 2H), 7.34-7.37 (d, 4H), 6.96-7.02 (t, 4H), 5.59 (s, 2H), 5.01 (s, 2H), 4.37-4.46 (m, 1H), 3.61 (s, 3H), 3.07-3.16 (m, 1H), 2.90-2.97 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[N:6]=[CH:5][N:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]([CH2:32][C@H:33]([OH:38])[C:34]([F:37])([F:36])[F:35])[C:28](=[O:31])[NH:29][N:30]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]([CH2:32][C@H:33]([OH:38])[C:34]([F:36])([F:37])[F:35])[C:28](=[O:31])[N:29]([CH2:2][C:3]3[CH:8]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]([F:18])([F:17])[F:16])[N:6]=[CH:5][N:4]=3)[N:30]=2)=[CH:22][CH:21]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: FC(F)(F)c1ccccc1-c1cc(CBr)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1n(Cc2cc(-c3ccccc3C(F)(F)F)ncn2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
37 mg (0.12 mmol) of the compound from Example 82A were dissolved in 2 ml of acetonitrile, and 39 mg (0.13 mmol) of the compound from Example 5A and 57 mg (0.18 mmol) of cesium carbonate were added. The mixture was stirred at 60° C. for 2.5 h. After cooling to RT, the solid was filtered off and rinsed with a little acetonitrile. The filtrate was concentrated under reduced pressure and directly purified chromatographically [Method 19]. The product obtained was subjected to a further chromatographic purification on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1, then 3:2). This gave 28 mg (41% of theory) of the target compound.