Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[Li]CCCC.[Cl:15][C:16]1[CH:17]=[C:18]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:19](N(OC)C)=[O:20].C(=O)(O)[O-].[Na+]>CCOCC.C1COCC1.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:19]([C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=2)=[O:20])[CH:25]=[C:26]([CH3:28])[N:27]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: CON(C)C(=O)c1cc(C)nc(Cl)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C(=O)c2cc(Br)cc(Br)c2)cc(Cl)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To 0.45 grams (1.4 mmol) of 1,3,5-tribromobenzene in 25.0 mL of anhydrous ether at −78° C. was added 0.57 mL of 2.5 M n-BuLi (1.4 mmol) at a rate that maintained the internal temperature of the reaction at less than −70° C. After the addition was complete, the reaction was stirred 1 hour at −78° C., then 0.220 grams (1.1 mmol) of 2-chloro-N-methoxy-6,N-dimethyl-isonicotinamide in 2 mL of THF was added, again keeping the temperature below −70° C. After the addition was complete, the reaction was allowed to stir at −25° C. for 45 minutes; then 100 mL saturated aqueous sodium bicarbonate was added and the reaction was stirred at room temperature for 30 minutes. The phases were separated and the aqueous phase was extracted with ether. The organic fractions were combined and dried with sodium sulfate. The volatiles were removed under reduced pressure and the crude product was chromatographed on silica gel using 5:1 hexane:ethyl acetate to give 330 mg (77% yield) of (2-chloro-6-methyl-pyridin-4-yl)-(3,5-dibromo-phenyl)-methanone.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:41][C@H:42]([C:50]([CH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15]([NH:41][C@H:42]([C:50]([CH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)CCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)CCc1ccccc1
Yield: 73.8 %

Procedure:
To a solution of Boc-D-Trp(CHO)-OH (0.92 g) in methylene chloride (15 ml) were added NMM (0.28 ml) and isobutyl chloroformate (0.36 ml) successively at -15° C., and the mixture was stirred for ten minutes. On the other hand, a solution of HCl.H-Phe-(CH2)2Ph (0.80 g) in methylene chloride (15 ml) was cooled at -30° C. and thereto was added NMM (0.28 ml). This solution was added to the above mentioned mixture at -50° C., and stirred for an hour at -50° C. and then stirred for 2 hours at room temperature. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with 2% hydrochloric acid, water, 2% sodium hydrogen carbonate solution, water, and saturated sodium chloride solution, and dried over magnesium sulfate. After evaporation, the residual white crystals were filtered and washed with n-hexane. The crystals were recrystallized from ethanol to give Boc-D-Trp(CHO)-Phe-(CH2)2Ph (1.16 g).
Reaction SMILES: O.[OH-].[Li+].OO.[NH2:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([CH2:17][C@@H:18]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)C(N2[C@@H](CC3C=CC=CC=3)COC2=O)=O)=[CH:9][C:8]=1[Cl:42].[O-]S([O-])=O.[Na+].[Na+].[C:49]([O-])([OH:51])=[O:50].[Na+]>O.C1COCC1>[NH2:6][C:7]1[C:12]([C:13]([F:16])([F:14])[F:15])=[CH:11][C:10]([CH2:17][C@@H:18]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:49]([OH:51])=[O:50])=[CH:9][C:8]=1[Cl:42]
Reactant: Nc1c(Cl)cc(C[C@@H](OCc2ccccc2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1C(F)(F)F
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C[C@@H](OCc2ccccc2)C(=O)O)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.34 g (8.0 mmol) lithium hydroxide hydrate and 1.38 mL (16 mmol, 35% in water) H2O2 in 25 mL water was added to a solution, cooled to 0° C., of 2.1 g (3.94 mmol) (S)-3-[(R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-benzyloxy-propionyl]-4-benzyl-oxazolidin-2-one in 50 mL THF and the reaction mixture was stirred for 2 h at 0° C. 5 mL of saturated Na2SO3 solution and 5 mL of saturated NaHCO3 solution were added, the mixture was stirred for another 30 min and then the THF was eliminated i.vac. The aqueous residue was extracted twice with 50 mL EtOAc in each case and the combined organic phases were dried over MgSO4. After the desiccant and solvent had been eliminated the crude product was further reacted without purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][N:9]2[N:12]=[C:13]([N+:15]([O-])=O)[CH:14]=[C:8]2[CH2:7]1)[CH3:5].[H][H]>CCO.[Pd]>[CH3:1][O:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][N:9]2[N:12]=[C:13]([NH2:15])[CH:14]=[C:8]2[CH2:7]1)[CH3:5]
Reactant: COCC(C)N1CCn2nc([N+](=O)[O-])cc2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCC(C)N1CCn2nc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A solution of 300a (600 mg, 2.5 mmol) in EtOH (40 mL) was added Pd/C (10%, 60 mg). The reaction mixture was charged with hydrogen gas (via balloon) and stirred at room temperature for 2 h. After reaction was complete, the mixture was filtered through a plug of CELITE®. The filtrate was concentrated reduced pressure to afford 300b as a yellow solid (467 mg, 89%), which was used without further purification. MS-ESI: [M+H]+ 211.1
Reaction SMILES: [OH:1][CH:2]1[C@@H:7]2[C:8]([CH2:11][OH:12])=[CH:9][CH2:10][C@@H:6]2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][O:3]1.FB(F)F.[CH2:21](OCC)C.C(=O)(O)[O-].[Na+].CCCCCC.C(OC(=O)C)C>CO>[OH:12][CH2:11][C:8]1[C@H:7]2[C@H:2]([O:1][CH3:21])[O:3][CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C@H:6]2[CH2:10][CH:9]=1
Reactant: COC(=O)C1=COC(O)[C@@H]2C(CO)=CC[C@H]12
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C1=CO[C@@H](OC)[C@@H]2C(CO)=CC[C@H]12
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
5 g (22.1 mmol) of methyl (4aS,7aS)-1-hydroxy-7-hydroxymethyl-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate was dissolved in 25 ml of methanol and catalytic amount of trifluoroboron diethylether was added thereto. The reaction mixture was stirred at room temperature for 20 hours and then the reaction was stopped by the addition of saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and distilled under vacuum. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethylacetate=5/1, v/v) to obtain 5.26 g (Yield 100%) of methyl (1R,4aS,7aS)-7-hydroxymethyl-1-methoxy-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=3[CH3:36])[CH2:25][CH2:24]2)=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([CH3:20])[CH3:19])[CH:12]=1)=[O:8].CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:75]1([C:78]2[O:79][CH:80]=[C:81]([C:83](O)=[O:84])[N:82]=2)[CH2:77][CH2:76]1>O.C(OCC)(=O)C>[Cl:22][C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([CH3:20])[CH3:19])[CH:12]=2)=[CH:21][C:2]([NH:1][C:83]([C:81]2[N:82]=[C:78]([CH:75]3[CH2:77][CH2:76]3)[O:79][CH:80]=2)=[O:84])=[C:3]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=3[CH3:36])[CH2:27][CH2:28]2)[CH:4]=1
Reactant: O=C(O)c1coc(C2CC2)n1
Reactant: Cc1ccc(C)c(N2CCN(c3cc(Cl)c(C(=O)NCc4cccc(CN(C)C)c4)cc3N)CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C)c(N2CCN(c3cc(Cl)c(C(=O)NCc4cccc(CN(C)C)c4)cc3NC(=O)c3coc(C4CC4)n3)CC2)c1
Temperature: 25 °C
Yield: 17.9 %

Procedure:
In a 40 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the 5-amino-2-chloro-N-(3-dimethylaminomethyl-benzyl)-4-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-benzamide 13b (142.50 mg, 0.28 mmol) was taken up in clean, dry N,N-dimethylformamide (3.00 ml, 38.74 mmol) and the mixture was stirred at room temperature under nitrogen until all solids were in solution. To this stirred solution was added the HATU (159.70 mg, 0.42 mmol) followed by the N,N-diisopropylethylamine (0.15 ml, 0.86 mmol) and the mixture was again stirred at room temperature until all solids were in solution. The 2-cyclopropyl-oxazole-4-carboxylic acid 1h (55.70 mg, 0.36 mmol) was added to the mixture and the reaction was allowed to stir over night at room temperature. The reaction was diluted with 15 ml of water and 15 ml of ethyl acetate. The layers were separated and the product was extracted from the aqueous using ethyl acetate (3×20 ml). The organic phases were combined and the solution was washed with brine (1×25 ml) and with saturated aqueous lithium chloride solution (2×25 ml). The solution was then dried over Na2SO4; the solution was decanted and the solvent was removed under reduced pressure. The resultant brown oil was then purified using silica gel column chromatography, eluting a gradient of 100% dichloromethane to 90% dichloromethane/9% MeOH/1% NH4OH. The desired product, 2-cyclopropyl-oxazole-4-carboxylic acid {4-chloro-5-(3-dimethylaminomethyl-benzylcarbamoyl)-2-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-amide 13c (33.60 mg, 0.05 mmol), was isolated as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14](=[S:18])[NH:13][C:12]=2[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14]([S:18][CH3:21])=[N:13][C:12]=2[CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)NC(=S)CCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSC1=Nc2cc(NC(=O)OC(C)(C)C)ccc2CCC1
Reaction time: 12 h
Yield: 42.1 %

Procedure:
A solution of (2-thioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)-carbamic acid tert-butyl ester (5.0 g, 17.1 mmol) and potassium carbonate (4.7 g, 34.0 mmol) in acetone (400 mL) was treated with iodomethane (2.5 mL, 5.7 g, 40.0 mmol). The mixture was stirred for 12 h and concentrated. The residue was partitioned between water (100 mL) and DCM (200 mL). The aqueous phase was extracted again with DCM and the combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography with DCM/MeOH (9:1) to give (2-methylsulfanyl-4,5-dihydro-3H-benzo[b]azepin-8-yl)-carbamic acid tert-butyl ester (2.2 g, 7.2 mmol, 42%): 1H NMR (300 MHz, CDCl3) δ 7.1 (m, 3H), 2.92 (t, 1H), 2.81 (t, 1H), 2.55 (s, 3H), 2.4 (q, 2H), 2.32 (q, 2H), 1.6 (s, 9H); MS (m/e) 307 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[Cl:19][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]=1[N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1
Reactant: O=C1NCCC12CCN(c1c(Cl)cncc1Cl)CC2
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1NCCC12CCN(c1c(Cl)cncc1-c1ccccc1)CC2
Yield: 28 %

Procedure:
General procedure E was followed using 8-(3,5-dichloropyridin-4-yl)-2,8-diazaspiro[4.5]decan-1-one E59 (38 mg, 0.13 mmol), phenyl boronic acid (19 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium(0) (7.3 mg, 5 mol %), acetonitrile (1.4 ml) and 0.5 M sodium carbonate (0.35 ml, 0.18 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 97:3) followed by preparative hplc (CH3CN, H2O, gradient 1:9 to 9:1) to furnish the title compound as a white solid (12 mg, 28%), along with recovered starting material as a clear colourless oil (10 mg, 23% RSM), LC-MS (ESI, 4 min) Rt 2.22 min, m/z 342 (100%, [M+H]+); m/z (ESI) C19H20N3ClO requires 341.1295, found [M+H]+ 341.1301.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[C:9]([C:11]1[C:20]([Cl:21])=[C:19]2[C:14]([C:15]([CH3:25])([CH3:24])[CH2:16][CH2:17][S:18]2(=[O:23])=[O:22])=[CH:13][CH:12]=1)=[O:10].[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.O>O1CCCC1>[Cl:21][C:20]1[C:11]([C:9]([C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[S:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:10])=[CH:12][CH:13]=[C:14]2[C:19]=1[S:18](=[O:23])(=[O:22])[CH2:17][CH2:16][C:15]2([CH3:25])[CH3:24]
Reactant: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Cl)CCCC1=O)c2Cl
Reactant: Sc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Sc3ccccc3)CCCC1=O)c2Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.7 g (1.75 mmol) of 1-chloro-2-(8-chloro-4,4-dimethyl-1,1-dioxothiochroman-7-yl)carbonylcyclohex-1-en-3-one were dissolved in 10 ml of tetrahydrofuran, and 0.19 g (1.75 mmol) of thiophenol and 0.19 g (1.92 mmol) of triethylamine were added dropwise. The mixture was stirred at 25° C. for two hours and then stirred into water, extracted with ethyl acetate and the organic phases were extracted with 1N hydrochloric acid, dried and concentrated. This gave 0.8 g of beige crystals.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[C:6](=[O:20])[NH:7][C:8](=[O:19])[N:9]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH:10]=1)#[N:4].ClCCl.[Cl:24][C:25]([Cl:29])([Cl:28])[S:26]Cl>O>[C:3]([C:5]1[C:6](=[O:20])[N:7]([S:26][C:25]([Cl:29])([Cl:28])[Cl:24])[C:8](=[O:19])[N:9]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH:10]=1)#[N:4]
Reactant: Cc1cccc(C)c1-n1cc(C#N)c(=O)[nH]c1=O
Reactant: ClSC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C)c1-n1cc(C#N)c(=O)n(SC(Cl)(Cl)Cl)c1=O
Temperature: 0 °C
Reaction time: 0.37 h

Procedure:
To an ice cold solution of 2.40 g of sodium hydroxide in 70 ml of water is added 14.46 g (0.06 mol) of 5-cyano-1-(2,6-dimethylphenyl)uracil. Then 100 ml of dichloromethane is added. To this mixture, at 5°, is added 6.6 ml (0.06 mol) of trichloromethane sulphenyl chloride in two volumes of dichloromethane. The mixture is stirred approximately 22 min at 5°. Then the phases are separated and the organic phase is washed with ice cold water. The dichloromethane solution is dried over magnesium sulphate, filtered and stripped. The residue is triturated with ether/petane, filtered and dried to obtain the crude product, which is then purified by crystallisation to yield 5-cyano-1-(2,6-dimethylphenyl)-3-trichloromethanesulphenyluracil, m.p. 223°-225°.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]1[NH:31][N:30]=[C:29]([CH2:32][C:33](O)=[O:34])[N:28]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:33](=[O:34])[CH2:32][C:29]1[NH:30][N:31]=[C:27]([CH3:26])[N:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(CC(=O)O)n[nH]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CC1
Product: COc1ccc(N2CCN(C(=O)Cc3nc(C)n[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC1CC1
Yield: 40 %

Procedure:
Prepared using the same procedure described in Example 189 from (S)-3-benzyl-1-(3-cyclopropoxy-4-methoxy-phenyl)-piperazine and (5-methyl-1H-[1,2,4]triazol-3-yl)-acetic acid to afford the title compound as colorless solid (53 mg, 40%). LC/MS (Method B) 3.02 min, [M+1]+ 462.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH:19]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:19]2[CH2:25][CH2:24][C:23](=[O:26])[NH:22][CH2:21][CH2:20]2)=[O:9])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Reactant: O=C1CCNCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCN1
Temperature: 0 °C

Procedure:
A solution of 20.00 g (109.52 mmol) of (E)-3-chlorocinnamic acid in 500 ml of dichloromethane was treated at RT with 6 drops of DMF. 10.08 ml (115.00 mmol) of oxalyl chloride in 60 ml dichloromethane were added dropwise and stirring was continued for 3 h30. The solution was evaporated, redissolved in 400 ml of dichloromethane, cooled (0° C.) and treated with a solution of 12.50 g (109.52 mmol) of [1,4]diazepan-5-one and 30.49 ml (219.05 mmol) of triethylamine in 190 ml of dichloromethane. The reaction was warmed up over night to RT and then evaporated. The precipitate was suspended in 90 ml of water, stirred 30 min, and filtered, washed with water to give, after drying under reduced pressure overnight, 28.03 g (92%) of the titled compound as a off-white powder. MS: 278.9 (MH+, 1Cl).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:12]\[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3]>[Pd].CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)/C=C(\c1ccc(S(C)(=O)=O)cc1)c1cc2cccnc2[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)CC(c1ccc(S(C)(=O)=O)cc1)c1cc2cccnc2[nH]1
Temperature: 50 °C
Yield: 25.5 %

Procedure:
A mixture of 2-[(E)-1-(4-methanesulfonyl-phenyl)-3,3-dimethyl-but-1-enyl]-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 73, 40 mg, 0.11 mmol) and 10% palladium on activated carbon (12 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 16 h. The mixture was cooled to 25° C., the catalyst filtered off, washed with ethyl acetate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[1-(4-methanesulfonyl-phenyl)-3,3-dimethyl-butyl]-1H-pyrrolo[2,3-b]pyridine (10 mg, 25%) as a white solid: LC/MS m/e calcd for C20H24N2O2S [M+H]+ 357.49, observed 357.4; 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (br. s., 1H), 7.84-7.93 (m, 3H), 7.65 (d, J=8.3 Hz, 2H), 7.05 (dd, J=7.7, 4.9 Hz, 1H), 6.43 (s, 1H), 4.41-4.47 (m, 1H), 3.04-3.15 (m, 3H), 2.40 (dd, J=14.0, 7.7 Hz, 1H), 1.99-2.06 (m, 1H), 0.91 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](OC2C=CC=CC=2)=[O:12])[N:7]([C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[CH:48]=[CH:47][C:35]([O:36][C:37]2[CH:42]=[CH:41][N:40]=[C:39]([C:43]([NH:45][CH3:46])=[O:44])[CH:38]=2)=[CH:34][C:33]=1[F:49].C(N(CC)CC)C>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:12])[NH:31][C:32]2[CH:48]=[CH:47][C:35]([O:36][C:37]3[CH:42]=[CH:41][N:40]=[C:39]([C:43](=[O:44])[NH:45][CH3:46])[CH:38]=3)=[CH:34][C:33]=2[F:49])[N:7]([C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C(=O)NC)c3)cc2F)c1
Yield: 57.6 %

Procedure:
A solution of ethyl 3-{3-tert-butyl-5-[(phenoxycarbonyl)amino]-1H-pyrazol-1-yl}benzoate (9.36 g, 22.0 mmol), 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide (5.0 g, 19.1 mmol; prepared as described in Dumas et al., PCT Int. Appl. WO 2004078748 (2004)) and triethyl amine (3.87 g, 38.3 mmol) in anhydrous THF (100 mL) was stirred at room temperature overnight. The crude product was purified by column chromatography (CH2Cl2 plus 1% to 3% of 2M NH3 in MeOH), followed by recrystallization from EtOAc/hexanes to give the desired product as an off-white crystalline solid (6.32 g, 57%). MS m/z 575.1 (M+H)+; calcd. mass 574. Retention time (LC-MS): 3.75 min. 1H-NMR (DMSO-d6): δ 8.97 (m, 1H); 8.89 (m, 1H); 8.80 (m, 1H); 8.52 (d, J=5.6 Hz, 1H); 8.16 (t, 1H); 8.06 (m, 1H); 7.99 (m, 1H); 7.85 (m, 1H); 7.71 (t, 1H); 7.39 (m, 1H); 7.33 (m, 1H); 7.17 (m, 1H); 7.06 (m, 1H); 6.42 (s, 1H); 4.36 (q, 2H); 2.78 (d, J=5.2 Hz, 3H); 1.31 (m, 12H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[N:9]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[O:11][C:7]=2[CH:6]=1)=[O:4].[Br-].[Al+3].[Br-].[Br-].O.Cl>CSC.ClCCl>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]2[O:11][C:7]3[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:25]=[CH:24][C:8]=3[N:9]=2)=[CH:15][CH:16]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1ccc2nc(COc3ccc(C(C)(C)C)cc3)oc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Solvent: CSC
Product: CC(C)(C)c1ccc(OCc2nc3ccc(C(=O)O)cc3o2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.6 %

Procedure:
To a solution of 2-(4-tert-butyl-phenoxymethyl)-benzoxazole-6-carboxylic acid methyl ester (67.8 mg, 0.20 mmol) in dimethyl sulfide (3 ml) and dichloromethane (3 ml) was added aluminum bromide (533.4 g, 2.0 mmol). The reaction mixture was stirred at room temperature for 2.5 h, after which water and 10% HCl were added. After stirring at room temperature for 1 h, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:EtoAc:MeOH=6:3:1) to give 2-(4-tert-butyl-phenoxymethyl)-benzoxazole-6-carboxylic acid as a white solid (50.5 mg, 77.7% yield).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[N:33]1[C:40]2[N:36]([N:37]=[C:38]([C:41]3[S:45][CH:44]=[N:43][CH:42]=3)[CH:39]=2)[CH:35]=[CH:34]1.[F:46][S:47]([F:60])([F:59])([F:58])([F:57])[C:48]1[CH:49]=[C:50]([CH:54]=[CH:55][CH:56]=1)[C:51](O)=[O:52]>CN(C=O)C>[CH3:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:51](=[O:52])[C:50]2[CH:54]=[CH:55][CH:56]=[C:48]([S:47]([F:60])([F:46])([F:57])([F:58])[F:59])[CH:49]=2)=[CH:28][C:27]=1[N:33]1[C:40]2[N:36]([N:37]=[C:38]([C:41]3[S:45][CH:44]=[N:43][CH:42]=3)[CH:39]=2)[CH:35]=[CH:34]1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cncs3)cc12
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cncs3)cc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
193 mg (0.51 mmol) of HATU and 62 mg (0.51 mmol) of 4-N,N-dimethylaminopyridine (DMAP) were added to a solution of 100 mg (0.34 mmol) of the compound of Example 89A and 92 mg (0.37 mmol) of 3-(pentafluoro-λ6-sulphanyl)benzoic acid in 2 ml of DMF. The reaction was stirred at RT for 20 h. The reaction mixture was then purified directly by preparative HPLC (Method 16). This gave 50.2 mg (27% of theory) of the title compound.