Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[OH:15][CH2:16][CH:17]1[O:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][CH2:18]1.[ClH:27]>>[ClH:1].[ClH:27].[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[C:2]([O:15][CH2:16][CH:17]3[O:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[O:19][CH2:18]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9][CH2:10]1
Reactant: OCC1COc2ccccc2O1
Reactant: CN1CCN(c2nccnc2Cl)CC1
Agent: Cl
Product: CN1CCN(c2nccnc2OCC2COc3ccccc3O2)CC1
Yield: 87 %

Procedure:
The title compound was prepared according to the procedure described in Example 90, Step 2, starting from 1-(3-chloro-2-pyrazinyl)-4-methylpiperazine (described in Example 169, Step 1) and 2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine. Yield 87%; mp 160-167° C. Anal. (C18H22N4O3.2 HCl) H, N; C: calcd, 52.06; found, 52.6.
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].[CH:5]1[C:17]2[CH:16]([CH2:18][O:19][C:20]([NH:22][C:23]([CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38])([CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[C:24]([O:26]CC)=[O:25])=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.O.Cl>CSC.ClCCl>[CH:14]1[C:15]2[CH:16]([CH2:18][O:19][C:20]([NH:22][C:23]([CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38])([CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[C:24]([OH:26])=[O:25])=[O:21])[C:17]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: C=CCCCC(CCCC=C)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: O
Solvent: CSC
Solvent: ClCCl
Product: C=CCCCC(CCCC=C)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A procedure previously described for dealkylation of esters was used after modifications (see Node et al., J. Org. Chem. 1981, 46, 1991): To a stirred solution of aluminum bromide (22.4 g, 84.0 mmol, 3.0 equiv.) in methyl sulfide (90 mL) was slowly added a solution of ethyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-(pent-4-enyl)hept-6-enoate 12 (12.7 g, 27.5 mmol) in dichloromethane (90 mL) at 0° C. over 15 min. The resulting mixture was allowed to warm to room temperature and stirred for 24 h. The reaction mixture was poured into water and acidified with a diluted HCl. The product was extracted with dichloromethane (2×100 mL) and the combined organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residual yellowish solid was purified by silica gel column chromatography (eluting with 7% methanol in dichloromethane) to give B5 as a white solid: 1H-NMR (400 MHz, CDCl3) δ 9.94 (bs, 1H), 7.78 (d, J=7.6 Hz, 2H), 7.61 (d, J=7.6 Hz, 2H), 7.41 (t, J=7.6 Hz, 2H), 7.33 (dt, J=7.6, 0.8 Hz, 2H), 5.75 (m, 2H), 5.00 (d, J=18.8 Hz, 2H), 4.96 (d, J=11.6 Hz, 2H), 4.42 (d, J=6.8 Hz, 2H), 4.23 (t, J=6.8 Hz, 1H), 2.34 (dt, J=12.8, 3.6 Hz, 2H), 2.04 (m, 4H), 1.82 (dt, J=12.8, 3.6 Hz, 2H) 1.40 (m, 2H), 1.17 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ 179.2, 154.2, 144.1, 141.6, 138.3, 128.0, 127.3, 125.2, 120.3, 115.2, 66.5, 64.1, 47.5, 35.2, 33.6, 23.5; HRMS (ESI) m/z for C27H31NO4 [M+H]+ calcd 434.2331. found 434.2334.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:14][S:15]SC.N(OC(C)(C)C)=O.O>C(Cl)(Cl)Cl>[CH3:14][S:15][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1cc(CO)cc(C(F)(F)F)c1
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CSc1cc(CO)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-amino-5-(trifluoromethyl)phenyl]methanol (319 mg, 1.67 mmol) (Step A, Example 24) in CHCl3 (5 mL) was added dimethyl disulfide (296 μL, 3.34 mmol). Next, t-butyl nitrite (285 μL, 2.4 mmol) was added dropwise by syringe. The reaction was stirred at room temperature for two hours and then poured into H2O (15 mL). The mixture was extracted with EtOAc (50 mL), washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 0% to 50% EtOAc/hexanes afforded [3-(methylthio)-5-(trifluoromethyl)phenyl]-methanol. The [3-(methylthio)-5-(trifluoromethyl)phenyl]methanol was contaminated with minor impurities that were removed after the next step. Rf=0.53 (50% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 7.63 (s, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 4.71 (s, 2H), 2.51 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][NH2:14])[O:9][C:8]=2[CH:15]=1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:31])[O:28]2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][NH:14][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]4[CH:25]=[CH:26][C:27](=[O:31])[O:28][C:29]=4[CH:30]=3)[O:9][C:8]=2[CH:15]=1
Reactant: O=c1ccc2ccc(OCCCBr)cc2o1
Reactant: COc1ccc2c(c1)O[C@@H](CN)CO2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)O[C@@H](CNCCCOc1ccc3ccc(=O)oc3c1)CO2
Temperature: 90 °C
Yield: 30.8 %

Procedure:
(S)-2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-methanamine hydrochloride (11.5 g, 49.8 mmole), 7-(3-bromopropoxy)coumarin (14.2 g, 50.0 mmole), and diisopropylethylamine (12 ml, 68.9 mmole) were combined in 350 ml of DMF and heated at 90° C. for 24 hours uunder a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 300 ml of dichloromethane. Upon addition of an equal volume of saturated aqueous sodium bicarbonate, a white solid precipitated. This was filtered and redissolved in 550 ml of warm methanol and 35 ml of 4N isopropanolic HCl was added. The solution was boiled on a hot plate and the solvent gradually replaced with isopropanol. Upon cooling, 0.54 g of the title compound precipitated as a white solid, monohydrochloride, quarter hydrate, m.p. 225°-227° C. Subsequent crops yielded as additional 6.1 g of product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](O)=[O:5].O>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1c(F)cc(F)cc1F
Solvent: O
Solvent: C1CCOC1
Product: OCc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a stirred solution of 4.1 grams (0.023 mole) of 2,4,6-trifluorobenzoic acid in 50 ml of anhydrous tetrahydrofuran, under a nitrogen atmosphere was added dropwise 4.0 grams (0.047 mole) of borane-tetrahydrofuran complex (as 46.6 ml of a 1.0 molar solution in tetrahydrofuran). The addition caused the reaction mixture to foam. Upon completion of addition the reaction mixture was stirred at ambient temperature for two hours, then was heated under reflux for one hour. The reaction mixture was cooled and 50 ml of water was cautiously added. The tetrahydrofuran was removed under reduced pressure and the residue washed into a separatory funnel with 100 ml of aqueous 2N sodium hydroxide. The mixture was extracted with three 100 ml portions of methylene chloride. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 3.2 grams of 2,4,6-trifluorophenylmethyl alcohol as an oil.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].N1C=CC=CC=1.O>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:27](=[O:28])[C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: O=C(Cl)c1cccs1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: ClCCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1cccs1
Yield: 47.2 %

Procedure:
2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.0 g) obtained from Referential Example 7 was suspended in 1,2-dichloroethane (20 ml), 2-thiophencarbonyl chloride (1.11 g) and pyridine (0.60 g) were added to the suspension, and the mixture was refluxed for 3 hours. The reaction mixture was allowed to cool, water was added to the mixture, extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 1.30 g of the title compound as a light yellow crystal.
Reaction SMILES: C[O-].[Na+].CO.[Cl:6][C:7]1[CH:31]=[CH:30][CH:29]=[C:28](Cl)[C:8]=1[C:9]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH3:19])=[C:13]([O:20][CH3:21])[C:12]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:10].[CH2:33](COC)[O:34]C>C(OCC)(=O)C.O>[Cl:6][C:7]1[C:8]([C:9]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH3:19])=[C:13]([O:20][CH3:21])[C:12]=2[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:10])=[C:28]([O:34][CH3:33])[CH:29]=[CH:30][CH:31]=1
Reactant: COCCOC
Reactant: CCCCCOc1c(OC)c(OC)cc(C)c1C(=O)c1c(Cl)cccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCOc1c(OC)c(OC)cc(C)c1C(=O)c1c(Cl)cccc1OC
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of sodium methylate in methanol (5.4 mol/l, 19.6 mmol), 2,6-dichloro-3',4'-dimethoxy-6'-methyl-2'-pentyloxy-benzophenone (obtained according to EP 0 727 141, 2.69 g, 6.5 mmol) and dimethoxyethane (20 ml) is heated to 80° C. with stirring for 24 hours. A mixture of water and ethyl acetate (1:1 v/v; 100 ml) is then slowly added at room temperature. The organic phase is separated and concentrated and the residue is purified by column chromatography (dichloromethane) yielding the pure product as a yellow oil, 0.52 g, (19.7%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][N:5]=1.[CH2:15](Br)[CH:16]=[CH2:17]>CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([Cl:3])=[N:5][CH:6]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Oc1cnc(Cl)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1cnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a stirring solution of NaH (0.334 g, 8.35 mmol) in DMF (10 mL) at 0° C. was added 1-chloroisoquinolin-4-ol (1 g, 5.57 mmol). The mixture was stirred at 0° C. for 10 min. before the addition of allyl bromide (0.808 g, 6.68 mmol) dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and then quenched with 1N HCl solution. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to get the crude material. The material was purified by flash chromatography with 20% of EtOAc/hexane to afford 4-(allyloxy)-1-chloroisoquinoline (1.0 g, 4.55 mmol, 83% yield) as a white solid. MS: MS m/z 220.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.[I-].[Na+].[C:32](=[O:35])([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH:7]=[C:8]([O:10][CH2:16][CH2:15][CH2:14][O:35][C:32]2[CH:26]=[CH:25][C:24]([C:21]3[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=3)=[CH:29][CH:28]=2)[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCCCOc2ccc(-c3ccccc3)cc2)cc(OCCCOc2ccc(-c3ccccc3)cc2)c1
Yield: 54.2 %

Procedure:
A mixture of 0.79 g (4.7 mmol) of 3,5-dihydroxybenzoic acid methyl ester, 3.0 g (10.3 mmol) of 4-(3-bromopropoxy)-1,1-biphenyl, 1.55 g (10.3 mmol) of sodium iodide and 3.9 g (28 mmol) of potassium carbonate in 80 mL of anhydrous acetone and 40 mL of DMF was stirred at reflux for 39 hours. The solvents were removed at reduced pressure, water was added to the residue and the product was extracted with chloroform. The dried extract was concentrated to a solid which was purified by chromatography on 90 g of silica gel using chloroform to give 1.5 g (54% yield, mp 142°-145°) of 3,5-bis [3-(1,1'-biphenyl-4-yloxy)propoxy]benzoic acid methyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][CH2:36][CH:37]([C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[OH:38]>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][CH2:36][CH:37]([OH:38])[C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)c1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccc(O)cc2)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4sulfonyl chloride, and 4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtained in 72% purity by HPLC. MS(ESI+): m/z=510.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:18].[Al+3].[Cl-].[Cl-].[Cl-].Cl.CCOC(C)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:18]
Reactant: COc1ccc(C(=O)c2ccc(Br)c(F)c2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(O)cc1)c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 112.1 %

Procedure:
To a stirred solution of (4-bromo-3-fluorophenyl)[4-(methyloxy)phenyl]methanone (185) (3.20 g, 10.4 mmol) in benzene (80 mL) was slowly added AlCl3 (5.91 g, 44.2 moL, 4.3 eq) via a powder addition funnel under a nitrogen atmosphere at room temperature. The stirred reaction mixture was heated at reflux for 3 h under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and then poured onto a mixture of 1 N HCl (150 mL) and ice (300 g). The quenched reaction mixture was transferred to a separatory funnel and EtOAc (200 mL) added. The organic phase was separated and the aqueous phase was extracted with EtOAc. The organic phase was washed with brine (200 mL), dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give 3.44 g of a brown solid. Crystallization from toluene yielded 2.68 g (88%) of the title compound 186 as a brown crystalline solid. 1H NMR (400 MHz, DMSO-d6): δ 6.91 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.2 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.69 (d, J=8.7 Hz, 2H), 7.89 (t, J=7.1 Hz, 1H), 10.54 (s, 1H).
Reaction SMILES: C([O:20][NH:21][C:22](=[O:55])[C@H:23]([NH:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:20][NH:21][C:22](=[O:55])[C@H:23]([NH:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=2)=[CH:44][CH:43]=1)(=[O:40])=[O:41])[CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37]
Reactant: O=C(NOC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NO)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
A solution of the title A compound, (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid O-tritylhydroxyamide (288 mg, 0.374 mmol) in 3 mL of dichloromethane is treated sequentially with triethylsilane (0.119 mL, 0.745 mmol) and trifluoroacetic acid (0.225 mL, 2.92 mmol) at 0° C. After 10 min, the solution is concentrated at 0° C. in a stream of nitrogen, and the residue is triturated from 5 mL of diethyl ether. The product is collected by vacuum filtration and dried to give 162.3 mg (82%) of (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid hydroxyamide as a white solid: m.p. 204-206° C. (dec); NMR(DMSO-d6) 1.24-1.33 (br m, 1H), 1.37-1.50 (br m, 3H), 3.39-3.47 (m, 2H), 3.52-3.62 (m, 1H), 7.53 (d, 2H, J=8.3), 7.70 (d, 2H, J=8.3), 7.80 (br s, 8H), 8.12 (d, 1H, J=8.5), 8.82 (br s, 1H), 10.56 (s, 1H); IR 1772, 1341, 1159; ESI-MS 528 (M++1).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].C([N+](C[CH2:23][CH2:24][CH3:25])(CCCC)CCCC)CCC.[OH-].[Na+].Cl[CH:29]=CC>O>[CH3:29][C:24](=[CH2:23])[CH2:25][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC=CCl
Reactant: CCCCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)COCCCCCC
Temperature: 70 °C
Reaction time: 7 h
Yield: 72 %

Procedure:
In a 3000 mL reaction flask was charged 1-hexanol (500 g, 4.9 mol), a 40% by weight in water solution of tetrabutyl ammonium hydroxide (65 g, 0.10 mol), and a 50% by weight solution of NaOH (480 g, 6.6 mol). The mixture was heated to 70° C. and 3-chloro-2-propene (530 g, 5.9 mol) was fed into the reaction over 3 hours. The reaction was aged for 7 hours at 70° C., and then cooled to room temperature. The reaction was quenched with 800 mL of water, and the layers separated. The organic layer washed with 800 mL water and 800 mL of brine. The crude product was purified by distillation to give 550 g of ether, a 72% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14](O)=[O:15])=[C:8]([CH3:20])[C:6]=2[N:7]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:14]([N:31]4[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]4)=[O:15])[CH:17]=[CH:18][CH:19]=3)=[C:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: OC1CCNCC1
Reactant: Cc1c(-c2cccc(C(=O)O)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(-c2cccc(C(=O)N3CCC(O)CC3)c2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with 4-hydroxypiperidine via General Procedure B to yield 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-hydroxypiperadin-1-yl)methanone. Crude 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-hydroxypiperadin-1-yl)methanone (72 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 29.5 mg of 425. MS (Q1) 555.2 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:14])[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:23])C=1.C(O)(=O)C1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:14])[C:9]([N+:11]([O-:23])([CH3:12])[CH3:13])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: CN(C)C(=O)C(O)c1cncc(Br)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1ccccc1
Solvent: ClCCl
Product: C[N+](C)([O-])C(=O)C(O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
A solution of 2-(5-bromo-pyridin-3-yl)-2-hydroxy-N,N-dimethyl-acetamide (100 mg, 0.387 mmol) in DCM (3.0 mL) was cooled in an ice water bath and treated with mCPBA (100.3 mg, 0.581 mmol). After stirring at room temperature for 4 h, the mixture was cooled and additional mCPBA was added (66.7 mg, 1 eq.). After stirring 18 h at room temperature, another 0.3 eq of mCPBA was added (13.3 mg). Finally after 4 h, the reaction was quenched by addition of 38% aqueous sodium bisulfite (100 uL) and the mixture was dried over Na2SO4. After filtration, MP—CO3 (1.74 mmol) was added to scavenge the benzoic acid by-product. After 5 d (3 hours is sufficient), the mixture was filtered and the resin was rinsed with 10% MeOH in DCM. The product was concentrated in vacuo to afford 2-(5-bromo-pyridin-3-yl)-2-hydroxy-N,N-dimethyl-acetamide N-oxide (97.0 mg, 91.7%). MS: m/z 275 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:17]([CH2:23][CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C=CC=CC=1>C1COCC1>[CH2:23](/[C:17](=[CH:4]\[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:24]
Reactant: O=Cc1ccccc1F
Reactant: CCOC(=O)C(CC)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1ccccc1F)CC

Procedure:
A solution of 2-fluorobenzaldehyde (6.2 g, 50 mmol) and ethyl 2-(triphenylphosphoranylidene)butanoate (18.8 g, 50 mmol) in THF (200 mL) was refluxed for 2 hrs. The reaction mixture was concentrated and the residue was triturated with 1:1 hexane:ethyl acetate. The precipitate was removed by filtration through silica gel and the filtrate was concentrated. The residue was purified by chromatography on silica gel eluting with 8:2 hexane:ethyl acetate to give ethyl (E)-2-ethyl-3-(2-fluorophenyl)propenoate.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1([CH3:24])[S:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[NH:11][C@H:10]1[C:21]([OH:23])=[O:22]>O>[C:1]([N:11]1[C@@H:10]([C:21]([OH:23])=[O:22])[C:9]([CH3:24])([CH3:8])[S:13][C@H:12]1[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)SC(c2ccc(F)cc2)N[C@H]1C(=O)O
Solvent: O
Product: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccc(F)cc1
Temperature: 100 °C

Procedure:
11.2 ml of acetic anhydride are portion-wise added to a suspension containing 5.1 g (20 mmoles) of 5,5-dimethyl-2-(4-fluorophenyl)-thiazolidine-4(S)-carboxylic acid in 11.2 ml of hot water. The mixture is heated at 100° C. for 5 minutes, then cooled down. The crystals are filtered out to give the title compound in a yield of 5.83 g (98%) which is recrystallized from the mixture of ethanol and ether, m.p.: 193.5° C., [α]D22 =-96.8° (c=0.62, methanol).