Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.C(OCC)(=O)C.C(COC)OC.CCCCCC.C(OCC)(=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: COc1cc(OC)cc(OCCCCl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: COCCOC
Product: COc1cc(OC)cc(OCCCN2CCC(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
A mixture of 5.51 g (0.019 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 4.42 g (0.019 mole) of 1-(3-chloropropoxy)-3,5-dimethoxybenzene and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g). The reaction mixture was stripped to dryness and the residue partitioned between chloroform-5% sodium hydroxide and chloroform-water. Removal of chloroform gave a brown oil. The oil was subjected to chromatography on a silica gel column using a gradient elution series of hexane-ethyl acetate and ethyl acetate-dimethoxyethane. After combining proper fractions eluted from the column and removing solvent, the residual oil was dried in vacuo overnight at 80° C. This produced 2.61 g (28.5%) of brown oil.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([CH3:31])=[O:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[Li+].[OH-]>>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[C:6]([NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([CH3:31])=[O:30])=[CH:19][CH:18]=1)=[O:15]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(C)=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Product: CS(=O)c1ccccc1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1

Procedure:
N-(2,6-dichlorobenzoyl)-4-[2-(methylsulfinyl)phenyl]-L-phenylalanine methyl ester (a mixture of two diastereomers) was hydrolyzed with LiOH as described for in Example 1-5) to yield N-(2,6-dichlorobenzoyl)-4-[2-(methylsulfinyl)phenyl]-L-phenylalanine (a mixture of two diastereomers). The mixture was taken up in CH2Cl2 and the solid was collected by filtration, washed with CH2Cl2, and dried to yield one diastereomer of N-(2,6-dichlorobenzoyl)-4-[2-(methylsulfinyl)phenyl]-L-phenylalanine (80 mg) (152A). ESMS: m/z 476 (MH+), 498 (M++Na), 474 (M−H)−. 1H-NMR (DMSO-d6): δ2.41 (s, 3H), 2.97 (m, 1H), 3.2 (dd, 1H), 4.72 (m, 1H), 7.32 (m, 3H), 7.4 (m, 5H), 7.6-7.7 (m, 2H), 8.0 (d, 1H), 9.15 (d, 1H). The filtrate was evaporated and the residue was crystallized from EtOAc/hexane to afford the other diastereomer of N-(2,6-dichloro-benzoyl)-4-[2-(methylsulfinyl)phenyl]-L-phenylalanine (44 mg) (152C). ESMS: m/z 476 (MH+), 498 (M++Na), 474 (M−H)−. −H-NMR (DMSO-d6): δ2.43 (s, 3H), 2.98 (m, 1H), 3.22 (m, 1H), 4.74 (m, 1H), 7.32 (m, 3H), 7.4 (m, 5H), 7.6-7.7 (m, 2H), 8.0 (d, 1H), 9.15 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH:15]1[CH2:18][CH:17]([N:19]([CH2:21][C@@H:22]2[C@@H:29]3[C@@H:25]([O:26][C:27]([CH3:31])([CH3:30])[O:28]3)[C@H:24]([N:32]3[C:36]4[N:37]=[CH:38][N:39]=[C:40]([NH:41][CH2:42][C:43]5[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:44]=5[O:51][CH3:52])[C:35]=4[CH:34]=[CH:33]3)[O:23]2)[CH3:20])[CH2:16]1>C(O)(=O)C>[C:8]([C:6]1[CH:5]=[CH:4][C:3]2[NH:12][C:13]([CH2:14][CH:15]3[CH2:16][CH:17]([N:19]([CH2:21][C@@H:22]4[C@H:29]5[O:28][C:27]([CH3:31])([CH3:30])[O:26][C@H:25]5[C@H:24]([N:32]5[C:36]6[N:37]=[CH:38][N:39]=[C:40]([NH:41][CH2:42][C:43]7[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:44]=7[O:51][CH3:52])[C:35]=6[CH:34]=[CH:33]5)[O:23]4)[CH3:20])[CH2:18]3)=[N:1][C:2]=2[CH:7]=1)([CH3:9])([CH3:11])[CH3:10]
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)C3CC(CC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)C3CC(Cc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
N-(2-amino-4-(tert-butyl)phenyl)-2-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)acetamide (272 mg, 0.374 mmol) was taken up in acetic acid (7.2 mL) and the solution was heated at 65° C. After 1.5 h, HPLC indicated the reaction was complete. The reaction was cooled to room temperature and the solvent removed under high vac. The residue was taken up in 35 mL CH2Cl2 and the organic phase was washed with 25 mL sat NaHCO3 solution and 20 mL 2% Na2CO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated to yield a light tan glass/stiff foam. The crude material was purified by flash chromatography (30 g silica gel; 4% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (224 mg, 84%) as a light tan glass which was a mixture of cis and trans diastereomers about the cyclobutyl ring: MS (ESI+) for C40H51N7O5 m/z 710.6 (M+H)+; MS (ESI−) for C41H51N7O5 m/z 708.7 (M−H)−; HPLC purity >95% (ret. time, 3.29, 3.33 min), two peaks observed due to diastereomers about the cyclobutyl ring.
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH:10]C(=O)C.Cl>CO>[Cl:1][C:2]1[C:7]([I:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH2:10]
Reactant: CC(=O)Nc1ccc(Cl)c(I)c1Cl
Agent: Cl
Solvent: CO
Product: Nc1ccc(Cl)c(I)c1Cl

Procedure:
To a solution of N-(2,4-dichloro-3-iodophenyl)acetamide (40.0 g, 121 mmol) in MeOH (100 mL) is added concentrated HCl (50 mL). The mixture is stirred and heated at reflux for 18 hours. The mixture is cooled and the solvents were removed under reduced pressure (water bath below 45° C.). The residue is cooled with an ice bath and 3N NaOH solution was added to adjust the pH to between 9 and 10. The mixture is extracted with ether and dried over MgSO4. The solvents were removed and the residue is purified through a flash chromatographic column with a gradient of hexanes/ether to give 2,4-dichloro-3-iodoaniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@:10]2([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:11](=[O:12])[C@@H:6]([C@:7]([CH3:28])([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C@@H:8]([O:18][CH2:19][O:20][CH3:21])[CH2:9]2)[C:5](=[O:29])[C:4]=1[Si](C)(C)C.[Li]N1C(C)(C)CCCC1(C)C.[C:45](Cl)(=[O:49])[CH:46]([CH3:48])[CH3:47].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:45]([C@:6]12[C:11](=[O:12])[C@:10]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])([CH2:9][C@H:8]([O:18][CH2:19][O:20][CH3:21])[C@@:7]1([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:3]([O:2][CH3:1])=[CH:4][C:5]2=[O:29])(=[O:49])[CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)C(=O)Cl
Reactant: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@H](C(=O)C([Si](C)(C)C)=C2OC)[C@]1(C)CCC=C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Product: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@](C(=O)C(C)C)(C(=O)C=C2OC)[C@]1(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 28.8 %

Procedure:
A 1 dram vial equipped with a stir bar is charged with 14.3 mg (0.030 mmol, 1 equiv.) of 51 and 150 μL of THF. The solution was cooled to −78° C. in a dry ice/acetone bath, and 300 μL of a solution of LiTMP (0.5M in THF, 0.150 mmol, 5 equiv.) was added dropwise. The yellow solution was stirred at −78° C. for 10 minutes followed by warming to 0° C. in a water/ice bath for 10 minutes and then recooling to −78° C. prior to addition of 15.7 μL (0.15 mmol, 5 equiv.) of isobutyryl chloride. The reaction was stirred 30 minutes prior to quenching by the addition of 500 μL of saturated aqueous ammonium chloride. The solution was transferred to a separatory funnel with 15 mL of hexane, and the organic layer was washed sequentially saturated aqueous 10% aqueous hydrochloric acid, water, and brine; dried with MgSO4; and concentrated in vacuo. The crude product was found to contain an inseparable mixture of product and 51. The mixture was purified by silica gel chromatography (Rf=0.25 in 9:1 hexane:ethyl acetate) and carried forward as a mixture. A 1 dram vial equipped with a stir bar is charged with 9.0 mg (0.016 mmol, 1 equiv.) of the mixture followed by 100 μL of THF. The vial was cooled in a water/ice bath and 18 μL of TBAF (1.0 M in THF, 0.018, 1.1 equiv.) is added. The mixture is stirred for 15 min at which time it is transferred to a separatory funnel, and the organic layer is washed sequentially saturated aqueous sodium bicarbonate, water, and brine. The organic layer is then dried with MgSO4 and concentrated in vacuo to give a yellow oil. The crude product is purified by preparative TLC (Rf=0.25 in 3:1 hexane:ethyl acetate) to give 4.1 mg (53% yield) of 56 as a clear oil. 1H NMR (500 MHz, CDCl3) δ 5.85 (s, 1H), 5.07-4.96 (m, 2H), 4.61 (dd, J=6.8, 15.5 Hz, 2H), 3.82 (s, 3H), 3.58 (dd, J=5.2, 11.3 Hz, 1H), 3.32 (s, 3H), 2.48 (ddd, J=7.5, 14.5, 34.2 Hz, 2H), 2.18-2.04 (m, J=5.9, 13.2, 17.3 Hz, 4H), 1.96 (s, 1H), 1.77 (dd, J=11.4, 13.4 Hz, 1H), 1.67 (d, J=3.0 Hz, 6H), 1.64 (s, 3H), 1.59 (s, 3H), 1.55 (s, 3H), 1.30-1.21 (m, J=2.6, 2.6 Hz, 1H), 1.14 (s, 3H), 1.12 (d, J=6.5 Hz, 3H), 1.05 (d, J=6.5 Hz, 3H). HRMS-ESI (m/z): [M+H]+ calculated for C28H42O6, 475.3054. found, 475.3045.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7]2=[CH:8][S:9][CH:10]=[C:6]2[N:5]=[C:4]1[S:11][CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:21]([O:1][CH2:2][N:3]1[C:7]2=[CH:8][S:9][CH:10]=[C:6]2[N:5]=[C:4]1[S:11][CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccnc(CSc2nc3cscc3n2CO)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccnc(CSc2nc3cscc3n2COC(C)=O)c1

Procedure:
1.3 g (4.2 mmol) of the title compound from Example 28 were dissolved in 25 ml of anhydrous pyridine, and 50 mg of 4-dimethylaminopyridine were added. Under a nitrogen atmosphere and while stirring, 6.3 ml acetic anhydride were added dropwise, and the mixture was stirred at room temperature for one hour. It was then poured onto ice water, extracted with methylene chloride, and the organic phase was dried over MgSO4 and concentrated in vacuo. The crystalline solid was recrystallized from ethanol. Melting point 111°-113° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]1[CH:29]=[CH:28][C:11]([CH2:12][O:13][C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:25]=O)[CH:21]=3)[N:16]([CH3:27])[CH:15]=2)=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:25][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:21]=3)[N:16]([CH3:27])[CH:15]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(COc2cn(C)c3ccc(C=O)cc3c2=O)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(COc2cn(C)c3ccc(CN4CCCC4)cc3c2=O)cc1
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
A solution of pyrrolidine (0.295 mL, 3.57 mmol) and 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-6-carbaldehyde (1.05 g, 3.25 mmol) in 1,2-dichloroethane (DCE) (50 mL) and 1 drop of acetic acid was treated with sodium triacetoxyborohydride (1.032 g, 4.87 mmol). The reaction mixture was stirred for 1.5 h, and was then concentrated under vacuum. The residue was taken in water (50 mL), and extracted with dichloromethane (2×50 mL). The organic layers were combined, washed with brine (50 mL), dried over sodium sulfate, and concentrated. The crude product was purified twice by automatic silica gel column chromatography (Combiflash RF), eluting with a mixture of [dichloromethane/methanol/ammonium hydroxide (80:20:2)]/dichlormethane (0-40%) to afford pure 3-((4-methoxybenzyl)oxy)-1-methyl-6-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one (1 g, 2.64 mmol, 81% yield) as a light yellow solid. LCMS: (M+H)+: 379.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]2[CH:16]=[CH:17][C:18]3[C:22]4[CH:23]=[CH:24][C:25]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=5[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:26][C:21]=4[S:20][C:19]=3[CH:41]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.CO>ClCCl.[Fe](Cl)(Cl)Cl>[CH3:34][O:33][C:30]1[CH:29]=[C:28]2[C:27](=[CH:32][CH:31]=1)[C:25]1[C:24](=[CH:23][C:22]3[C:18]4[CH:17]=[C:16]5[C:15](=[CH:41][C:19]=4[S:20][C:21]=3[CH:26]=1)[C:6]1[C:7](=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9]1[C:14]5=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:40]1[C:35]2=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COc1ccc(-c2ccc3c(c2)sc2cc(-c4ccc(OC)cc4-c4ccccc4)ccc23)c(-c2ccccc2)c1
Agent: Cl[Fe](Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)c1ccccc1c1cc3c(cc21)sc1cc2c4ccc(OC)cc4c4ccccc4c2cc13
Reaction time: 1 h
Yield: 92.6 %

Procedure:
In a 1000 ml three-necked flask that had been deaerated and filled with nitrogen, 4.4 g (8.1 mmol) of 3,7-bis(5-methoxybiphenyl-2-yl)dibenzo[b,d]thiophene was dissolved in anhydrous dichloromethane (400 ml), 13.2 g (81 mmol) iron(III)chloride was then added, and the mixture was stirred one hour. Methanol 200 ml were added to the mixture and the organic layer was separated and the solvent removed in vacuum. The residue was purified by column chromatography on silica(hexane-dichloromethane) afforded a white solid (4.1 g, 7.5 mmol, 93%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC.[OH-].[Na+]>[F:12][C:2]([F:1])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][N:8]=1
Reactant: OCc1ccc(C(F)(F)F)nc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc(C(F)(F)F)nc1
Reaction time: 1.5 h
Yield: 44.8 %

Procedure:
A solution of [6-(trifluoromethyl)pyridine-3-yl]methanol (0.886 g, 5.0 mmol) in DCM (20 ml) was added to a mixture of Dess-Martin periodinane (2.334 g, 5.5 mmol) in DCM (20 ml) at rt. The reaction was stirred for 1.5 hrs then diluted with Et2O (100 ml) and 4N NaOH (15 ml). The mixture was stirred for 10 mins then separated. The organic layer was washed with 4N NaOH (15 ml) then brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 15% EtOAc/hexanes) to give the aldehyde (0.392 g, 45%). 1HNMR (400 MHz, CDCl3): δ 7.89 (1H, d, J 8.1), 8.37 (1H, d, J 8.1), 9.20 (1H, s), 10.22 (1H, s).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:7]=2[N:6]=[C:5]1[Cl:17])[CH:2]=[CH2:3].Br[CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:27])([CH3:29])[CH3:28])([CH3:24])[CH3:25])[C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:7]=2[N:6]=[C:5]1[Cl:17])[CH:2]=[CH2:3]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CC
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2CC
Temperature: 60 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a solution of 7-allyl-8-chloro-3-ethyl-1H-purine-2,6(3H,7H)-dione (6.8 g, 26.77 mmol) in DMF (50 mL) was added (3-bromopropoxy)(tert-butyl)dimethylsilane (8 g, 31.75 mmol), followed by potassium carbonate (5 g, 36.23 mmol) and TBAI (5 mg, 0.014 mmol). The reaction was stirred at 60° C. overnight. The reaction was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum/ethyl acetate (15:1 to 1:1) to give 7-allyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-8-chloro-3-ethyl-1H-purine-2,6(3H,7H)-dione (5.88 g, 51.6% yield) as a colorless oil. LCMS retention time 2.224 min; LCMS MH+ 427.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:23]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3)=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OO
Reactant: O=C1CCc2cc(OCCCSc3ccccc3)ccc2N1
Product: O=C1CCc2cc(OCCCS(=O)c3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-[3-(phenylmercapto)-propoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:11]1[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])=[O:10].ClC1C=C(C=CC=1)C(OO)=[O:27]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:11]1[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])(=[O:27])=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(S(=O)c2ccc(Cl)cc2Cl)s1
Solvent: ClCCl
Product: CC(=O)c1cc([N+](=O)[O-])c(S(=O)(=O)c2ccc(Cl)cc2Cl)s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 71.7 %

Procedure:
To a solution of 1-[5-(2,4-dichlorophenyl)sulfinyl-4-nitro-2-thienyl]ethanone (100 mg, 0.275 mmol) in dichloromethane (2 mL), m-chloroperoxybenzoic acid (95 mg, 0.55 mmol) was added slowly at 0° C. The mixture was stirred at ambient temperature for 10 hours. Then the mixture was diluted with dichloromethane (10 mL) and washed with aqueous sodium bicarbonate solution (5 mL×3), then water (5 mL×2) and brine (5 mL). The organic phase was dried (Na2SO4), concentrated under vacuum and the residue was purified by chromatography to afford the title product (75 mg, 72% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.62 (1H, s), 8.32 (1H, d), 8.0 (1H, s), 7.87 (1H, m), 2.67 (3H, s). MS m/z: 378.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]([CH2:39][OH:40])[CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:40][CH2:39][CH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:16][CH2:15][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:19][CH2:18]3)[CH:21]=2)=[O:27])[CH2:31]1
Reactant: OCC1CNc2ccccc21
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CC(CO)c5ccccc54)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
100 mg (0.25 mmol) of 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 50 mg (0.32 mmol) (2,3-dihydro-1H-indol-3-yl)-methanol in 50 μL (0.27 mmol) TEA and 0.90 mL DMF were combined with 85 mg (0.27 mmol) TBTU and the mixture was stirred for 5 h at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and evaporated down by roughly half. The precipitated solid was suction filtered and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1.C([Li])(C)(C)C.C([S@@]([N:22]=[CH:23][CH2:24][CH2:25][C:26]([CH3:38])([CH3:37])[C:27](OCC1C=CC=CC=1)=[O:28])=O)(C)(C)C>C1COCC1.CCCCC.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]([CH:23]2[NH:22][C:27](=[O:28])[C:26]([CH3:38])([CH3:37])[CH2:25][CH2:24]2)=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1
Reactant: CC(C)(CCC=N[S@@](=O)C(C)(C)C)C(=O)OCc1ccccc1
Reactant: Fc1cc(Br)cc(F)c1F
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)CCC(c2c(Br)cc(F)c(F)c2F)NC1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-bromo-3,4,5-trifluorobenzene (313 mg, 1.48 mmol) in THF (3 mL) at −78° C. was added tert-butyllithium (1.74 mL of a 1.7 M solution in pentane, 2.96 mmol) dropwise. The reaction mixture was stirred for 1 h at −78° C., 3 h at 0° C., and then cooled back down to −78° C. A solution of benzyl (SS)-5-[(tert-butylsulfinyl)imino]-2,2-dimethylpentanoate (250 mg, 0.741 mmol, described in Intermediate 3) in toluene (5 mL) was added. The reaction mixture was stirred for 20 min at −78° C., 16 h at ambient temperature, and 1 h at reflux. The solvent was removed in vacuo and the crude solid dissolved in DMSO (5 mL). The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=337 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=3[CH2:10][CH2:9]2)[CH2:2]1.Br[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=3[CH2:10][CH2:9]2)[CH2:2]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCNC1)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(Cc3ccc4ccccc4c3)C1)CC2

Procedure:
Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 2-bromomethyl-naphthalene analogously to Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=2)[N:8]=[CH:7]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:28]1[CH2:29][CH2:30][N:25]([C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[CH2:5][N:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=3)[N:8]=[CH:7]2)[CH2:26][CH2:27]1
Reactant: CCOC(=O)c1ccc2ncn(Cc3cccc(Br)c3)c(=O)c2c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2ncn(Cc3cccc(N4CCOCC4)c3)c(=O)c2c1
Temperature: 120 °C

Procedure:
To a microwave vial was added ethyl 3-(3-bromobenzyl)-4-oxo-3,4-dihydroquinazoline-6-carboxylate (0.06 g, 0.16 mmol) and morpholine (0.040 mL, 0.47 mmol) in anhydrous 1,4-dioxane (3 mL). The solution was degassed under nitrogen for 10 min then cesium carbonate (0.15 g, 0.46 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.027 g, 0.047 mmol) were added followed by tris(dibenzylideneacetone)dipalladium(0) (0.021 g, 0.023 mmol). The reaction mixture was heated at 120° C. for 30 min in a microwave. The mixture was then concentrated and to the residue was added dichloromethane (3 mL) and water (1 mL). After separation, the aqueous layer was extracted with dichloromethane (3 mL). The combined organic layers were then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give ethyl 3-(3-morpholinobenzyl)-4-oxo-3,4-dihydroquinazoline-6-carboxylate. LC-MS: (FA) ES+ 394.