Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl.[CH3:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH:18]=1>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:18]2[N:19]([N:26]3[C:34](=[O:35])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:36])[C:20]3[C:25]([C:17]=2[CH3:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cn(N2C(=O)c3ccccc3C2=O)c2ccccc12
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C(=O)c2ccc(F)cc2)n(N2C(=O)c3ccccc3C2=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 8.14 ml of 4-fluorobenzoyl chloride and 450 ml of dry DCM was cooled in an ice/salt bath to 0° C. To the stirred solution was added 7.74 ml of tin (IV) chloride. The mixture was stirred at -5° C. to 0° C. for 10 minutes after which was added 18.0 g of 2-[(3-methyl-1H-indol-1-yl]-1H-isoindole-1,3-(2H)dione (Example 10b). The reaction mixture was stirred at 0° C. for 1.5 hours, allowed to warm to room temperature for 2 hours, cooled again in an ice bath, poured onto ice, extracted twice with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated to a yellow solid. Chromatography (15% acetone/heptane) provided a solid weighing 56.8 g. Recrystallization from ethyl alcohol gave 21.1 g of the product, m.p. 227°-228° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:10])([CH3:9])[C:3]=1[CH2:11][CH2:12][C:13](=[O:15])[CH3:14].[OH-].[K+].[NH4+].[Cl-].[CH2:20]1C[O:23][CH2:22][CH2:21]1>O>[CH3:14][C:13]([OH:15])([CH2:12][CH2:11][C:3]1[C:4]([CH3:9])([CH3:10])[CH:5]([CH3:8])[CH2:6][CH2:7][C:2]=1[CH3:1])[C:20]#[C:21][CH2:22][OH:23]
Reactant: C1CCOC1
Reactant: CC(=O)CCC1=C(C)CCC(C)C1(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Product: CC1=C(CCC(C)(O)C#CCO)C(C)(C)C(C)CC1
Reaction time: 3 h
Yield: 77 %

Procedure:
A mixture of 4-(2,5,6,6-tetramethyl-1-cyclohexen-1-yl)-2-butanone (13 g, 0.061 mol) and propargylic alcohol (4 g, 0.071 mol) was added within 100 min to a mechanically stirred slurry of powdered KOH (26 g, 0.46 mol) in THF (100 ml) at 20° C. under N2. After 3 h at 20°, the brown mixture was poured into a cold solution of NH4Cl (28 g) in H2O (100 ml). Extraction with ether, workup and chromatography [SiO2, (200 g), cyclohexane/ethyl acetate 7:3] afforded 4-methyl-6-(2,5,6,6-tetramethyl-1-cyclohexen-1-yl)-2-hexyn-1,4-diol as a viscous pale-yellow oil (12.3 g, 77%).
Reaction SMILES: Cl.[Cl:2]C1C=CC2OC=C(CCC[N:13]3[CH2:18][CH2:17][N:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)C=2C=1.S(O[CH2:40][CH2:41][C:42]1[C:43]2[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:44]=2[O:45][CH:46]=1)(C1C=CC(C)=CC=1)(=O)=O.COC1C(N2CCNCC2)=NC=CC=1>>[ClH:2].[Cl:51][C:49]1[CH:48]=[CH:47][C:44]2[O:45][CH:46]=[C:42]([CH2:41][CH2:40][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:17][CH2:18]3)[C:43]=2[CH:50]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2coc3ccc(Cl)cc23)cc1
Reactant: COc1cccnc1N1CCN(CCCc2coc3ccc(Cl)cc23)CC1
Agent: COc1cccnc1N1CCNCC1
Agent: Cl
Product: COc1cccnc1N1CCN(CCc2coc3ccc(Cl)cc23)CC1

Procedure:
The title compound was prepared (0.55 g, 63%, mp 217°-220° C.) in a manner analogous to the preparation of 1-[3-(5-chlorobenzo[b]furan-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)piperazine (Example 25) by the reaction of 5-chloro-3-benzo[b]furanethanol tosylate with 1-(3-methoxy-2-pyridinyl)piperazine.
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CI.[C:32](O)(=O)C.[OH-].[Na+]>O1CCCC1.C1OCCOCCOCCOCCOCCOC1.O>[N:1]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])([CH3:32])[C@@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH2:3][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CC(=O)O
Reactant: O=C(N[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CN(C(=O)OCc1ccccc1)[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 90 %

Procedure:
To a suspension of KH (19.3 g, 25% suspension in oil, mmol) in tetrahydrofuran (100 mL) at 0° C. was slowly added (over 25 min) a solution of Cbz-D-Cha-Pro-OH (16.8 g, 41.7 mmol) in tetrahydrofuran (50 mL). During this addition period the internal temperature was monitored and maintained at less than 10° C. To this solution was then slowly added a solution of methyl iodide (5 mL, 80 mmol) and 18-crown-6 (661 mg, 2.5 mmol), again maintaining the internal temperature below 10° C. After 2 h acetic acid (10 mL) was added dropwise, followed by water (10 mL). The solution was then poured into cold water and the pH was adjusted to 9 with 2N NaOH. The aqueous base was washed twice with diethyl ether and then acidified to pH 2 with conc. HCl and extracted four times with chloroform. The chloroform extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo to afford 15.7 g (90%) of a pale yellow solid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[S:21]2(=[O:36])=[O:35])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])(=[O:3])[CH3:2].[C:44]([O:48][C:49](=[O:60])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][NH2:59])=[CH:53][CH:52]=1)([CH3:47])([CH3:46])[CH3:45].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(Cl)Cl.CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[C:44]([O:48][C:49](=[O:60])[CH2:50][C:51]1[CH:52]=[CH:53][C:54]([CH2:57][CH2:58][NH:59][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[S:21]3(=[O:36])=[O:35])=[CH:16][CH:15]=2)=[CH:55][CH:56]=1)([CH3:45])([CH3:47])[CH3:46]
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)[C@H](Cc4ccccc4)NC(C)=O)C(=O)O)cc3)S2(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(CCN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)[C@H](Cc4ccccc4)NC(C)=O)C(=O)NCCc4ccc(CC(=O)OC(C)(C)C)cc4)cc3)S2(=O)=O)cc1
Reaction time: 3 h

Procedure:
The title C compound, (S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid (83.4 mg, 0.137 mmol) is dissolved in DMF (2 mL) and a solution of [4-(2-amino-ethyl)phenyl]-acetic acid t-butyl ester (32.2 mg, 0.137 mmol) in CH2Cl2 (0.5 mL) is added followed by a solution of HOBt (21.9 mg, 0.143 mmol) in DMF:CH2Cl2 (50:50, 0.5 mL), and finally EDCl (27.6 mg, 0.143 mmol) and TEA (0.020 mL, 0.143 mmol) as a slurry in CH2Cl2 (0.5 mL). The reaction is mixed well to give a homogeneous solution. After 3 h, EtOAc (100 mL) is added and the reaction is washed three times with 2N aqueous HCl (50 mL) and saturated aqueous NaHCO3 (50 mL). EtOAc layer is dried over anhydrous Na2SO4 and concentrated to yield {4-[2-((S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionylamino)-ethyl]-phenyl}-acetic acid t-butyl ester as an oil.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[N+:25]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Cl)([O-:27])=[O:26]>C1C=CC=CC=1.C(#N)C>[C:15]([C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[N+:25]([O-:27])=[O:26])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: c1ccccc1
Product: CCOC(=O)CC(Cc1ccccc1[N+](=O)[O-])(C(=O)OCC)C(=O)OCC
Reaction time: 1 h

Procedure:
A 500 ml. Morton flask equipped with a condenser, stirrer, and dropping funnel was flame dried and charged with NaH (11.9 g - 61% dispersion in mineral oil; 0.3 mole) and 150 ml. of 10% DMF in benzene. Triethyl 1,1,2-ethanetricarboxylate (73.9 g; 0.3 mole) was then added with vigorous stirring over a one hour period. After stirring at room temperature for 0.5 hour, there was then added as rapidly as possible o-nitrobenzyl chloride (51.5 g; 0.3 mole). The resulting reaction mixture was heated at reflux for 23 hours. After cooling, insoluble material was removed by filtration (supercel). Water was added to the filtrate followed by aqueous HCl to acidify the aqueous layer. Extraction with ether followed. The combined ethereal extracts were then washed twice with water, once with brine, dried over Na2SO4, filtered and rendered free of solvent in vacuo. The viscous oil so obtained was dissolved in acetonitrile and washed with n-pentane to remove the mineral oil. Removal of the acetonitrile afforded the crude product. The IR (infrared) and NMR (nuclear magnetic resonance) spectra were consistent with the structure and this material was used directly in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][C@H:16]3[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:29][C:30]1[C:31]([F:37])=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>O1CCOCC1.C(#N)C>[ClH:2].[ClH:29].[Cl:29][C:30]1[C:31]([F:37])=[C:32]([NH:33][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][C@H:16]4[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Nc1cccc(Cl)c1F
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O[C@H]1CCCNC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4.0M HCl in dioxane (6.0 ml) was added to a stirred suspension of tert-butyl (3S)-3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate (3.21 g) and 3-chloro-2-fluoroaniline (0.98 ml) in acetonitrile (50 mL). The reaction mixture was heated at 80° C. and left at this temperature overnight. The solvent was evaporated and the residue purified by flash column chromatography eluting with increasingly polar mixtures of methylene chloride/7N ammonia solution in methanol (97/3 to 95/5) to give N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-amine dihydrochloride as a solid (3.20 g); 1H NMR Spectrum: (DMSO d6) 1.56 (m, 2H), 1.72 (m, 1H), 2.12 (m, 1H), 2.48-2.59 (m, 2H), 2.82 (m,1H), 3.20 (m, 1H), 3.95 (s, 3H), 4.49 (m, 1H), 7.26 (s, 1H), 7.28 (m, 1H), 7.47 (m, 1H), 7.53 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.63(s, 1H); Mass Spectrum: (M+H)+ 403.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.CN(C)[CH:18]=[CH:19][C:20](=[O:26])[CH:21]=[CH:22]N(C)C.Cl>O>[CH3:15][CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH:22]=[CH:21][C:20](=[O:26])[CH:19]=[CH:18]3)=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: CN(C)C=CC(=O)C=CN(C)C
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Agent: Cl
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (101 mg), 1,5-bis(dimethylamino)-1,4-pentadien-3-one (84 mg) and hydrochloric acid (1N, 0.5 ml) in water (1.5 ml) was stirred at room temperature for 4 hours. More hydrochloric acid (1N, 0.5 ml) was added and the reaction mixture was stirred at room temperature for 18 hours and then under reflux for 4 hours to afford a quantity of red insoluble material. The hot aqueous solvent was decanted off from the insoluble material, was allowed to cool and was seeded to afford the title compound, 41 mg, m.p. 245°-249° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH2:7][NH2:8].[N-:10]=[N+:11]=[N-].[Na+]>CN(C=O)C>[N:8]([CH2:7][C:6]1[CH:5]=[C:4]([Cl:9])[S:3][C:2]=1[Cl:1])=[N+:10]=[N-:11]
Reactant: NCc1cc(Cl)sc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(Cl)sc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
C-(2,5-dichloro-thiophen-3-yl)-methylamine: To 103A (250 mg, 1.016 mmol) in DMF (4 mL) was added sodium azide (661 mg, 10.16 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated yielding 3-azidomethyl-2,5-dichloro-thiophene (135 mg). To a solution of this intermediate (135 mg, 0.519 mmol) in methanol (5 mL) was added 10% palladium on carbon. The reaction mixture was stirred at rt under a hydrogen balloon for 1 h. The mixture was filtered and the catalyst was washed with MeOH. The combined filtrate was concentrated and the resulting residue was dissolved in 0.25 N HCl (2 mL) and washed with EtOAc (10 mL). The aqueous layer was basified with 1N NaOH and extracted with EtOAc (5×10 mL). The combined organic layers were washed with brine, dried with Na2SO4, filtered and concentrated yielding 103B (41 mg). LCMS m/z 182.1 (M+H)+.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][C:13]1[O:17][N:16]=[C:15]([C:18](=[O:20])[CH3:19])[CH:14]=1>C1COCC1>[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][C:13]1[O:17][N:16]=[C:15]([C:18]([OH:20])([C:1]#[CH:2])[CH3:19])[CH:14]=1
Reactant: C#C[Mg]Br
Reactant: CC(=O)c1cc(COC2CCCCO2)on1
Solvent: C1CCOC1
Product: C#CC(C)(O)c1cc(COC2CCCCO2)on1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of ethynylmagnesium bromide (2.93 mL of a0.5M solution in THF, 1.47 mmol) at 0° C. was slowly added 1-{5-[(oxan-2-yloxy)methyl]-1,2-oxazol-3-yl}ethanone (220 mg, 0.98 mmol) in THF (5 mL). The reaction mixture was allowed to warm to RT and stirred for 45 minutes. The reaction mixture was quenched with aqueous saturated NH4Cl solution (10 mL) and the organics were removed in vacuo. The product was extracted into EtOAc (20 ml×2) and the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute column, 10-30% EtOAc in heptanes) to give the title product as a pale yellow oil: 1H NMR (250 MHz, CDCl3) delta 1.93-1.40 (9H, m), 2.66 (1H, s), 2.85 (1H, s), 3.69-3.46 (1H, m), 3.93-3.79 (1H, m), 4.94-4.54 (3H, m), 6.38 (1H, s); LC-MS: m/z=+251.95 (M+H)+.
Reaction SMILES: Br[C:2]1[S:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[S:19][C:5]3[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:9](=[O:10])[C:4]=3[C:3]=2[CH3:20])=[CH:24][CH:23]=1
Reactant: COC(=O)CCn1c(=O)c2c(C)c(Br)sc2n(C)c1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)CCn1c(=O)c2c(C)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Temperature: 100 °C
Yield: 46.5 %

Procedure:
To a solution of methyl 3-(6-bromo-1,5-dimethyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (180 mg, 0.498 mmol) in toluene (5 mL) was added 4-chlorophenylboronic acid (78 mg, 0.498 mmol) and aq. Cs2CO3 solution (1 M, 1 mL). The reaction was degassed under nitrogen gas (3×) then Pd(PPh3)4 (10 mg) was added. The reaction was heated at 100° C. for 18 h, cooled to RT then diluted with EA (10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with DCM/MeOH (80:1) to give methyl 3-(6-(4-chlorophenyl)-1,5-dimethyl-2,4-dioxo-1,2-dihydro thieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (91 mg, 46.5% yield) as a yellow solid. LCMS: MH+ 393 and TR=1.956 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[CH:11][N:10]([CH3:24])[C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: CI
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ncn(C)c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10.0 g. 4,5-bis(4-methoxyphenyl)imidazole in 100 ml of dimethylformamide was treated with 2.4 g of a 50% sodium hydride dispersion and then 8.0 g of methyl iodide was added dropwise. Stirring at room temperature was continued overnight and the reaction mixture was poured onto ice water. The product was collected by filtration and recrystallization from hot 1-chlorobutane gave 7.0 g of 4,5-bis(4-methoxyphenyl)-1-methyl-1H-imidazole, m.p. 121.5°-122°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[I:12].[H-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])[CH:6]=[C:5]2[I:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1cc2[nH]cc(I)c2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(I)c2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.4 %

Procedure:
To a solution of 5,6-difluoro-3-iodo-1H-indole (Intermediate 27; 930 mg; 3.33 mmol) in THF (20 mL) at 0° C. was added NaH (266.4 mg; 60%; 6.66 mmol) under nitrogen. The reaction mixture was stirred at r.t. for 15 minutes before a solution of benzenesulfonyl chloride (763.4 mg; 4.32 mmol) in THF (2 mL) was added dropwise. The reaction was stirred at r.t. for 12 hours, quenched with an ice-water mixture (60 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by a silica gel chromatography (petroleum ether/EtOAc=10/1-3/1) to afford 1.01 g (72%) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC=CC=1>[O:15]([C:13]1[C:12]2[C:7]([N:6]=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccccc1
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: c1ccc(Oc2c3ccccc3nc3ccccc23)cc1
Temperature: 60 °C
Reaction time: 84 h
Yield: 97.9 %

Procedure:
Dry benzene (450 mL) was added to 1.50 g acridone (1 equiv.) under N2-atmosphere. SOCl2 (3.37 mL, 6 equiv.) was added and the reaction mixture was refluxed over night followed by removal of solvent by evaporation. Dry DMF (75 mL), phenol (2.17 g, 3 equiv.) and K2CO3 (4.26 g, 3 equiv.) were added under N2. The reaction was stirred at 60° C. for 3.5 days. After filtration and evaporation the crude product was purified using flash chromatography (CH2Cl2 to CH2Cl2:Et2O, 6:1) giving 2.04 g of 2, 98% yield. 1H NMR (CDCl3): 8.28 (5+4, br ddd, J=8.9, 1.1, 0.8 Hz, 2H), 8.11 (8+1, ddd, J=8.7, 1.3, 0.8 Hz, 2H), 7.79 (6+3, ddd, J=8.9, 6.6, 1.3 Hz, 2H), 7.47 (7+2, ddd, J=8.7, 6.6, 1.1 Hz, 2H), 7.28 (2′+4′, m, 2H), 7.06 (3′, m, 1H), 6.86 (1′+5′, m, 2H). 3.40 (6, m, 2H).
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[N:13]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([OH:27])=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.[ClH:28].[C:29]1([C:35]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C@H:43]3[C@H:39]([CH2:40][NH:41][CH2:42]3)[C@@H:38]([OH:44])[CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>ClCCl.CC(C)=O.C(OCC)C.C(N(CC)CC)C>[ClH:28].[C:45]1([C:35]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:43]3[C@H:39]([CH2:40][N:41]([C:25](=[O:27])[CH2:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[N:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)[CH2:42]3)[C@@H:38]([OH:44])[CH2:37][CH2:36]2)[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Reactant: O=C(O)Cc1ccccc1N1CCCC1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1N1CCCC1)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Temperature: 4 °C
Reaction time: 1 h

Procedure:
0.42 cm3 of triethylamine and 0.49 g of carbonyl-diimidazole are added to a solution, cooled to +4° C., of 0.86 g of the hydrobromide salt of (2-pyrrolidinophenyl)acetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for one hour at 4° C. and then a solution of 1 g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride and 0.42 cm3 of triethylamine in 10 cm3 of dry dichloromethane, is added. The reaction mixture is stirred at room temperature for 24 hours, and then washed twice with 10 cm3 of water and then with an aqueous solution of sodium hydrogen carbonate, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The product, which is obtained in the form of a base, is converted to the hydrochloride by dissolving in the minimum amount of acetone, by treating with a solution of hydrochloric acid in ethyl ether, and by adding ethyl ether. The solid obtained is triturated in ethyl ether and then dried. 0.2 g of (3aR,4S,7aR)-7,7-diphenyl-2-[(2-pyrrolidinophenyl)acetyl]-4-perhydroisoindolol hydrochloride is obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[O:21])[CH:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH3:15])[CH:7]=[CH:6]2.[BH4-].[Na+]>CO>[CH3:20][S:17]([O:16][CH:14]([CH3:15])[CH:13]([OH:21])[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)(=[O:19])=[O:18]
Reactant: COc1ccc2cc(C(=O)C(C)OS(C)(=O)=O)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2cc(C(O)C(C)OS(C)(=O)=O)ccc2c1

Procedure:
Representative of Scheme III is the reaction of 1-(6-methoxy-2-naphthyl)-2-methanesulfonyloxypropan-1-one with sodium borohydride in methanol to yield 1-hydroxy-1-(6-methoxy-2-naphthyl)prop-2-yl methanesulfonate. Treating that material with sodium acetate in acetic acid affords 2-(6-methoxy-2-naphthyl)propanal, which is oxidized with sodium chlorite to 2-(6-methoxy-2-naphthyl)propionic acid. By employing the optically active (S) 1-(6-methoxy-2-naphthyl)-2-methanesulfonyloxypropan-1-one there is obtained, following the same sequential steps, (S) 2-(6-methoxy-2-naphthyl)propionic acid.