Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:20])[C@H:6]([CH3:19])[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]([CH3:19])[C:5]([O:4][CH3:3])=[O:20])(=[O:9])=[O:10])=[CH:12][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@H](C)NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.60 g, 11.0 mmol) in dimethylformamide (20.0 mL), is added N-[4-methoxybenzenesulfonyl]-alanine methyl ester (2.6 g, 10.0 mmol) in dimethylformamide (10.0 mL). After stirring at room temperature for 30 minutes, benzyl bromide (1.22 mL, 10.0 mmol) is added, and the reaction is stirred for two hours at room temperature. The reaction is then partitioned between ether and brine, the organic layer is dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (20% ether/hexanes) to give methyl 2-[[4-methoxybenzenesulfonyl]-(benzyl)amino]-propionoate.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.[H-].[Na+].O>CN(C)C=O>[CH2:7]([N:6]1[C:2]([O:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[C:3]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[C:4]([CH3:9])=[N:5]1)[CH3:8]
Reactant: CCn1nc(C)c(C(=O)c2ccccc2)c1Cl
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(C)c(C(=O)c2ccccc2)c1Oc1ccc(OC)cc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 57.3 %

Procedure:
A mixture of 129 mg of (5-chloro-1-ethyl-3-methyl-1H-pyrazol-4-yl)-phenyl-methanone, 141 mg of 4-methoxyphenol and 33 mg of sodium hydride (60% in mineral oil) in 3 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 110° C. for 5 h. Water (8 ml) was added and the mixture was extracted three times with 10 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40–60° C.) (1:3) for the elution to give 100 mg of [1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone as a yellow oil. Mass spectrum (ES) m/z 337 [M]+, 378 [M+H+CH3CN]+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][CH2:14][CH2:15][CH2:16][SH:17].[Na]>>[N+:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[S:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH:6]=[O:7])([O-:12])=[O:11]
Reactant: CCCCS
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na]
Product: CCCCSc1ccc(C=O)cc1[N+](=O)[O-]

Procedure:
4-Chloro-3-nitrobenzaldehyde (25.0 g) was added to a solution of sodium n-butylthiolate (1 equiv; prepared by addition of n-butylthiol to an equimolar amount of sodium dissolved in absolute alcohol) in absolute alcohol (300 ml) and the mixture was heated under reflux for 4 hr. On cooling, the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel with dichloromethane elution to give 3-nitro-4-(n-butylthio)benzaldehyde as yellow crystals, mp 93° C. Pmr spectrum (CDCl3 ; δ in ppm): 0.99 (3H, t); 1.66 (4H, m); 3.04 (2H, t); 7.56 (1H, d); 8.05 (1H, dofd); 8.69 (1H, d); 10.00 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([OH:19])=O)[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([N:38]3[CH2:37][CH2:36][N:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:41])([F:42])[F:27])[CH:30]=4)[CH2:40][CH2:39]3)=[O:19])[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: COc1cccc(S(=O)(=O)N2CC(C(=O)O)N(c3ccccc3)C2=O)c1
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)N3CCN(c4cccc(C(F)(F)F)c4)CC3)N(c3ccccc3)C2=O)c1

Procedure:
In analogy to example 1, (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid (step 4 of example 1) was reacted with N-(3-trifluoromethylphenyl)-piperazine to give the title compound as a colorless solid. MS: 588.5 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[H-].[Na+].I[CH2:20][CH3:21]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:20][CH3:21])=[CH:10][CH:9]=2)[CH:15]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2F)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2cc(Br)ccc2F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 70.8 %

Procedure:
To a solution of 4-(5-bromo-2-fluoro-benzyl)-phenol (6.0 g, 21.0 mmol) in anhydrous N,N-dimethylformamide (20 mL) cooled at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.02 g, 25.6 mmol). After stirring at 0° C. for 45 minutes, iodoethane (2.08 mL, 25.6 mmol) was added dropwise and the resulting mixture was allowed to warm up to room temperature. After 18 hours, the reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were washed twice with water and once with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography over silica gel eluting with a gradient of 0 to 10% ethyl acetate in heptane to afford 4.6 g (58% yield) of the desired product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([S:4]([NH:6][C:7]1([C:11](=[NH:13])[NH2:12])[CH2:10][O:9][CH2:8]1)=[O:5])[CH3:3].CN(C)/[CH:17]=[CH:18]/[CH:19]=O.C[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:3][C:2]([S:4]([NH:6][C:7]1([C:11]2[N:12]=[CH:19][CH:18]=[CH:17][N:13]=2)[CH2:10][O:9][CH2:8]1)=[O:5])([CH3:14])[CH3:1]
Reactant: CN(C)/C=C/C=O
Reactant: CC(C)(C)S(=O)NC1(C(=N)N)COC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)NC1(c2ncccn2)COC1
Reaction time: 0.17 h

Procedure:
To a yellow solution of 3-(1,1-dimethylethylsulfinamido)oxetane-3-carboximidamide (crude from above, assumed 0.494 mmol) in MeOH (2 ml) in a 50 ml sealed tube was added (E)-3-(dimethylamino)acrylaldehyde (0.090 g, 0.912 mmol), and the reaction mixture stirred for 10 min. Sodium methoxide (0.43 ml, 1.824 mmol, 25 wt % in MeOH) was added to the mixture, which was then stirred at 65° C. for overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was back extracted with ethyl acetate (3×25 ml). The combined organic layers was washed with saturated brine solution, dried over Na2SO4, filtered and concentrated. The crude material was purified by pre-HPLC. Overall yield of two steps: (30 mg, 24%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:25]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[CH2:12]2)=[O:9])=[N:6][CH:7]=1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[CH:27]1([C:25]([N:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=3)[CH2:16][CH:11]([NH:10][C:8]([C:5]3[CH:4]=[CH:3][C:2]([C:38]4[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=4)=[CH:7][N:6]=3)=[O:9])[CH2:12]2)=[O:26])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCc1ccc(C2CC(NC(=O)c3ccc(Br)cn3)CN(C(=O)C3CCCC3)C2)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CCc1ccc(C2CC(NC(=O)c3ccc(-c4cccc(C(F)(F)F)c4)cn3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
59 mg (0.12 mmol) of 5-bromo-N-[1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidin-3-yl]pyridine-2-carboxamide (Example 82) and 27 mg (0.14 mmol, 1.2 eq.) of [3-(trifluoromethyl)phenyl]boronic acid were reacted according to General Method 7. Yield: 46 mg (71% of theory)
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12](=[O:23])[N:13]([CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[C:6]([CH3:24])[C:5]=1[N:25]([S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:26]>CCCCCC.CCOC(C)=O>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([S:27]([N:25]([CH3:26])[C:5]2[C:6]([CH3:24])=[CH:7][C:8]([CH:10]=[CH:11][C:12](=[O:23])[N:13]([CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][C:4]=2[C:3]([OH:38])=[O:2])(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: CCCCCCCCN(C)C(=O)C=Cc1cc(C)c(N(C)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCN(C)C(=O)C=Cc1cc(C)c(N(C)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)O)c1
Yield: 91.5 %

Procedure:
In the same manner as described in Example 18, 188 mg (0.35 mmol) of the product of Example 205 provided 170 mg (93%) of the desired carboxylic acid as a white solid after trituration with Hexane/EtOAc (2:1). Electrospray Mass Spec 575(M+HCOOH--H).
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[C:3](=[O:13])[C:4]1[C:9]([C:10]2=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:14]([N:21]([CH3:26])[CH2:22][CH2:23][NH:24][CH3:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[OH:1][C:11]1[C:10](=[O:12])[C:9]2[C:4]([C:3](=[O:13])[C:2]=1[N:24]([CH3:25])[CH2:23][CH2:22][N:21]([CH3:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1c2ccccc2C(=O)C2OC12
Reactant: CNCCN(C)Cc1ccccc1
Solvent: CCO
Product: CN(CCN(C)C1=C(O)C(=O)c2ccccc2C1=O)Cc1ccccc1
Reaction time: 20 h

Procedure:
A mixture of 2.61 g of 2,3-epoxy-2,3-dihydro-1,4-naphthoquinone, 2.67 g of N-benzyl-N,N'-dimethylethylenediamine and 150 ml of absolute ethanol was stirred for 20 hours, then concentrated to one-half its original volume and refrigerated overnight. The solvent was removed, the residue dissolved in dichloromethane and passed through a pad of hydrous magnesium silicate and silica, eluting first with dichloromethane, then with 1% methanol in dichloromethane. The active fraction was flash chromatographed eluting with dichloromethane followed by 2% methanol in dichloromethane. The active fraction was evaporated and the residue triturated in dichloromethane/hexane giving 900 mg of the desired product, mp 121°-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:25]2([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:32]>C(OCC)C.O1CCOCC1>[ClH:1].[ClH:32].[NH2:17][CH:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH:9]([C:25]2([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(c2ccc(Cl)c(Cl)c2)C2(O)CCCCC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NC1CCN(CC(c2ccc(Cl)c(Cl)c2)C2(O)CCCCC2)CC1
Reaction time: 16 h
Yield: 82 %

Procedure:
A solution of tert-butyl {1-[2-(3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate (130 mg, 0.28 mmol) (Example 13), in diethyl ether (2 mL) was treated with a 4 N solution of hydrogen chloride in dioxane (1 mL). The resulting solution was stored at 25° C. for 16 h, during which time crystals began to form. The mixture was transferred to the refrigerator where it was stored for an additional 16 h. The resulting crystals were collected, washed with diethyl ether, and dried in vacuo to yield 101 mg (82%) 1-[2-(4-aminopiperidin-1-yl)-1-(3,4-dichlorophenyl)ethyl]cyclohexanol dihydrochloride as a white solid. MS m/z 371/373/375 ([M+H]+); HRMS: calcd for C19H28Cl2N2O.2.00 HCl, 442.1112; found (ESI), 371.1642.
Reaction SMILES: I[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:17]2[N:25]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:5]1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:16][O:15][C:9]1[N:8]=[C:7]2[C:6]([C:17]3[N:25]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)(=[O:28])=[O:27])[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[CH:18]=3)=[CH:5][N:4]([CH2:3][CH2:2][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:12]2=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1cc2c(nc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCI
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(nc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCN1CCOCC1
Temperature: 60 °C
Reaction time: 48 h
Yield: 99.1 %

Procedure:
Stir bisazaindole iodide 18 (52 mg, 0.0862 mmol), morpholine (1.10 equiv., 8.26 mg, 8.3 μL, 0.0948 mmol) and K2CO3 (13 mg, 0.0942 mmol), with heating at 60° C. in CH3CN (6 mL) under N2, for 24. LC-MS shows that the reaction is only 50% complete. Add extra morpholine (17 μL) and continue stirring at 60° C. After 48 h, the reaction medium is concentrated under vacuum and the residue is submitted to flash chromatography to give 19 (48 mg, 99%) as a white solid: 1H NMR (CDCl3) δ 8.38 (dd, 1H, J=4.5, 1.2 Hz), 7.75 (dd, 1H, J=4.5, 1.2 Hz), 7.68 (d, 2H, J=8.4 Hz), 7.62 (s, 1H), 7.14 (m, 2H), 7.05 (d, 2H, J=8.4 Hz), 7.02 (s, 1H), 4.28 (t, 2H), 4.05 (s, 3H), 4.0 (s, 3H), 3.74 (m, 4H), 2.90 (t, 2H), 2.55 (m, 4H), 2.29 (s, 3H). TLC (MeOH at 4%/CH2Cl2, 0.25% of NH3) Rf=0.65, m/z obs.=562.15 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:14])[CH2:11][C@@H:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:33][C@@H:34]([CH:44]([CH3:46])[CH3:45])[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Mg].BrCCBr.[Cl-].[NH4+]>O1CCCC1.C(OCC)C.C(OC)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C@@H:13]([OH:14])[CH2:33][C@H:34]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:44]([CH3:45])[CH3:46])[CH2:11][C@@H:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](CBr)COCc1ccccc1
Reactant: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H](C=O)N2C(=O)OC(C)(C)C)ccc1OC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H]([C@@H](O)C[C@H](COCc3ccccc3)C(C)C)N2C(=O)OC(C)(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1.98 g of aldehyde 7 in 15 mL of tetrahydrofuran is cooled to 10° C. and is treated with the Grignard reagent prepared by treating 1.23 g of ((S)-2-bromomethyl-3-methylbutoxymethyl)-benzene with 0.12 g of magnesium in diethylether containing 0.043 g of 1,2-dibromoethane at 45° C. The reaction is stirred for 90 minutes at room temperature, then 20 mL of a 25% aqueous solution of ammonium chloride is added, followed by addition of 20 mL of tert-butylmethyl ether. The organic phase is separated and washed twice with 20 mL of water. The organic phase is concentrated in vacuum to give the crude alcohol 8 as an oil. Purification on silica-gel delivers e.g. 0.97 g of pure 8. A negative [a]d is found at c=1, CHCl3. M++H=628, M++H+Na=650.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.Br[C:14]1C=C(C)C=CC=1OC.COB(OC)OC>>[CH3:12][O:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:14])=[CH:7][C:6]=1[B:8]([OH:10])[OH:9]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: COc1ccc(C)cc1Br
Agent: COB(OC)OC
Product: COc1ccc(C)cc1B(O)O
Yield: 96 %

Procedure:
This compound was prepared in a manner similar to that of 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) from 2-bromo-4-methylanisole (2.00 g, 9.94 mmol), n-BuLl (2.5M in hexanes; 4.00 mL, 10 mmol), and trimethylborate (3.4 mL, 30 mmol) to afford 1.60 g (96%) of 2-methoxy-5-methylphenylboronic acid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:25]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:32]3[CH:33]=[CH:34][C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:30][CH:31]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(NC(=O)c1coc(Oc2ccc(C(C)(C)C)cc2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 51.4 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 4-tert-butyl phenol (40 mg, 0.26 mmol) to give the title compound (33 mg, 51%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:11](Cl)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Br:14][C:15]1[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[C:18]([Br:27])[C:16]=1[NH2:17]>C(#N)C>[CH3:1][C:2]1[S:3][C:4]([C:11]([NH:17][C:16]2[C:18]([Br:27])=[CH:19][C:20]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:21][C:15]=2[Br:14])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: Cc1nc(C(F)(F)F)c(C(=O)Cl)s1
Reactant: Nc1c(Br)cc(OC(F)(F)F)cc1Br
Solvent: CC#N
Product: Cc1nc(C(F)(F)F)c(C(=O)Nc2c(Br)cc(OC(F)(F)F)cc2Br)s1
Yield: 98.9 %

Procedure:
2-Methyl-4-trifluoromethyl-5-chlorocarbonyl thiazole 6.47 g and 2,6-dibromo-4-trifluoromethoxy aniline 8.91 g were added in acetonitrile 16.8 ml, and they were heated to reflux for 6.5 hours. Solvent was removed from the reaction mixture by distillation under a reduced pressure, and then ethyl acetate 420 ml and water 300 ml were added and they were agitated. After standing calmly, the ethyl acetate layer was collected, and washed with water, saturated sodium bicarbonate solution, and water (300 ml each) in succession. Then, after drying over anhydrous sodium sulfate, solvent was removed by distillation under a reduced pressure, to obtain thifluzamide 13.9 g.
Reaction SMILES: [IH:1].[CH2:2]1[O:10][CH:3]1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OCC)C>[I:1][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:2][OH:10]
Reactant: c1ccc(C2CO2)cc1
Reactant: I
Solvent: CCOCC
Product: OCC(I)c1ccccc1
Temperature: 0 °C

Procedure:
A 250 ml round bottom flask was charged with 21 ml HI (55% aqueous solution) and cooled to 0° C. Via an addition funnel, 20 grams of styrene oxide in 80 ml of diethylether were added over a one hour period. Diethylether (45 ml) was added and the water phase was separated. The leftover organic solution was dried with Na2SO4 and evaporated. Thirty-eight grams of a faint yellow solid were obtained having a melting point of 71-72° C.
Reaction SMILES: I[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH2:29]([OH:32])[C:30]#[CH:31]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([C:31]#[C:30][CH2:29][OH:32])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: Ic1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCC#Cc1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of N-(4-(3-iodopyridin-2-yloxy)phenyl)pyridin-2-amine (0.300 g, 0.771 mmol), copper(I) iodide (3.91 μL, 0.116 mmol), trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.034 g, 0.048 mmol), triethylamine (0.800 mL, 5.74 mmol) and propargyl alcohol (0.150 mL, 2.54 mmol) in THF (5 mL) was stirred at rt under an atmosphere of argon for 3.5 h. The reaction was evaporated onto silica gel and purified by flash chromatography (Isco, (60 gram)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97). The material was stirred over MeOH, filtered and dried in vacuo to give a white crystalline solid. MS (ESI, pos. ion) m/z: 318.0. IC50 (uM)=0.2612.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.C(B(CC)[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)C.[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:2]2[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: CCB(CC)c1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCCOc1ccc(-c2cccnc2)cc1
Temperature: 25 °C

Procedure:
In a nitrogen atmosphere, 2-(4-bromophenoxy)ethanol 500 mg, diethyl (3-pyridyl) borane 509 mg, finely pulverized potassium hydroxide 388 mg, tetra-n-butyl ammonium bromide 74 mg and a tetrakis-triphenyl phosphine palladium complex 133 mg were added to tetrahydrofuran 10 ml and stirred under reflux with heating. After stirring for 2 hours, the mixture was cooled to room temperature and partitioned by adding water and ethyl acetate. The organic layer was washed with water and then with brine, dried over magnesium sulfate anhydride, and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound (233 mg, 50%) was obtained as a pale yellow crystalline.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=2)[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=2)[CH:22]=[CH:21]1.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=2)[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1ccc2ccccc2c1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3ccc4ccccc4c3)c2c1

Procedure:
The titled compound (31 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2-(chloromethyl)naphthalene according to the method of the process (7) of Example 4.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:35])[C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:34])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)=[CH:16][CH:15]=1)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:35])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:34])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)c1ccc(C(=O)NCCCCNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: NCCCCNC(=O)c1ccc(C(=O)NCCCCN)cc1
Reaction time: 8 h

Procedure:
{4-[4-(4-tert-Butoxycarbonylamino-butylcarbamoyl)-benzoylamino]-butyl}-carbamic acid tert-butyl ester (0.49 g) is treated with neat TFA (5 mL) and allowed to stand at RT overnight. The acid is removed in vacuo to afford the title compound as a yellow solid. Alternatively, deprotection can be carried out using 33% HBr is acetic acid. [M+H]+ 307.22