Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O>>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([C:37]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[C:27]([O:30][CH3:31])[CH:26]=3)[N:20]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: COc1ccc(N)c(C(N)=O)c1
Reactant: COc1cccc(C=O)c1
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccc(OC)cc3c(=O)[nH]2)c1
Yield: 41.3 %

Procedure:
According to the preparation of 42, 10 (1.0 g, 6.0 mmol) and 3-methoxybenzaldehyde (34) (0.8 g, 6.0 mmol) were used to afford 52 (0.7 g, 42.4%) as pale yellow needles.
Reaction SMILES: COC1C=CC([N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11](O)[C:10]2=[S:21])=CC=1.C(=S)([O-:24])N>C(Cl)Cl>[C:14]1([C:12]2[NH:11][C:10](=[S:21])[N:9]([OH:24])[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC([O-])=S
Reactant: COc1ccc(-n2cc(-c3ccccc3)n(O)c2=S)cc1
Solvent: ClCCl
Product: On1cc(-c2ccccc2)[nH]c1=S

Procedure:
The thiohydroxamine acid, 3-(p-methoxyphenyl)-5-phenyl-1-hydroxy-1,2-dihydroimidazole-2-thione, was prepared from the thiocarbamate in a manner similar to that used in Example I. The 3-(p-methoxyphenyl)-5-phenyl-1-hydroxy-1,2-dihydroimidazole-2-thione was recrystallized from methylene chloride/hexane to give white crystalline material. mp: 168° C. (dec); IR (CH2Cl2): 2800-1756-1510-1383-1361-1241-1133 cm-1 ; 1H NMR (200 MHz, CDCl3 : DMSO 1:1): 3.82 (3H, OCH3, s); 6.5 (2H, d); 7.15 (1H, CH=, s); 7.4 (3H, m); 7.54 (2H, d); 7.71 (2H, d); 11.85 (1H, OH, br); 13C NMR (CDCl3 : DMSO 1:1): 54 (OCH3): 110.6 (CH=); 112.6 (CH); 125.6 (CH); 125.7 (CH); 127 (CH); 127.2 (CH); 129.5 (Cq); 157.6 (CH); Anal. Calcd for C16H14N2O2 5: C, 64.40; H, 4.73; N, 9.39; S,10.74 Found C, 64.48; H, 4.24; N,9.43; S, 10.68.
Reaction SMILES: Br[C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[O:17][CH2:18][O:19][CH3:20].[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd-4](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)C=CC=CC=1.COCCOC>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=3)[C:3]=2[O:17][CH2:18][O:19][CH3:20])=[CH:24][CH:23]=1
Reactant: CCCc1cc2cc(OC)ccc2c(OCOC)c1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCc1cc2cc(OC)ccc2c(OCOC)c1-c1ccc(F)cc1
Yield: 95.8 %

Procedure:
2-Bromo-6-methoxy-1-methoxymethoxy-3-propyl-naphthalene (95) (1.26 g, 3.71 mmol), 4-fluorobenzeneboronic acid (1.04 g, 7.43 mmol), tetrakis(triphenylphosphino)palladium (0) (0.43 g, 0.371 mmol), 2 M sodium carbonate (20 mL) and ethylene glycol dimethyl ether (20 mL) were added in a sealed tube and reacted as described above to give 1.26 g (95%) of the title compound (225) as oil. 1H NMR (400 MHz, d-CDCl3): δ 0.80 (t, J=7.3 Hz, 3H), 1.43-1.45 (m, 2H), 2.50 (t, J=7.8 Hz, 2H), 3.11 (s, 3H), 3.93 (s, 3H), 4.73 (s, 2H), 7.10-7.15 (m, 4H), 7.29-7.32 (m, 2H), 7.43 (s, 1H), 8.00 (d, J=8.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18]C)[C:12]=2[C:11]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[N:10]1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)=[N:10]1
Reactant: CNC(=O)c1ccc(-c2nn(-c3c(F)cccc3F)c3ccnc(OC)c23)cc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: CNC(=O)c1ccc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of 4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-methylbenzamide (2.68 g) in acetonitrile (50 mL) were added sodium iodide (2.04 g) and chloro(trimethyl)silane (4.34 mL) was added, and the mixture was stirred at 60° C. for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate to ethyl acetate/methanol). 1.60 g of the obtained title compound (2.15 g) was dissolved in 2-propanol (240 mL) at 80° C. To the solution was added heptane (160 mL) over 15 min, the mixture was stirred for 15 min, and allowed overnight to be cooled. The white precipitate was collected by filtration, washed with a mixed solvent of 2-propanol-heptane (3:4), and dried in vacuum to give the title compound (1.49 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:7]([CH2:8][C@@H:9]([C:11](O)=[O:12])[NH2:10])=[CH:6][NH:5]2>C1COCC1>[NH2:10][CH:9]([CH2:8][C:7]1[C:14]2[C:4](=[CH:3][C:2]([F:1])=[CH:16][CH:15]=2)[NH:5][CH:6]=1)[CH2:11][OH:12]
Reactant: N[C@@H](Cc1c[nH]c2cc(F)ccc12)C(=O)O
Solvent: C1CCOC1
Product: NC(CO)Cc1c[nH]c2cc(F)ccc12
Temperature: 0 °C
Yield: 117.5 %

Procedure:
6-Fluorotryptophan (1.9 g, 9.153 mmol) was dissolved in THF (50 mL) and cooled to 0° C. in an ice bath. BH3.Me2S complex (2.55 mL, 26.87 mmol) was added and the reaction mixture was heated at reflux for 21 h. The reaction mixture was then cooled in an ice bath and cautiously quenched by the dropwise addition of MeOH (5 mL). The crude reaction mixture was then concentrated in vacuo. The crude product was dissolved in EtOAc (50 mL) and extracted with aqueous NaOH (20% w/v, 2×50 mL) after which the combined aqueous fractions were extracted with EtOAc (2×50 mL), and the combined organic fractions were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (2.24 g, quantitative) as a white semi-solid that was used without further purification. δH (CD3OD) 7.28 (1H, dd, J 8.9 and J 5.5 Hz), 6.85 (1H, s), 6.83 (1H, dd, J 10.0 and J 2.3 Hz), 6.57 (1H, dt, J 8.1 and J 8.6 Hz), 3.37 (1H, dd, J 10.7 and J 4.3 Hz), 3.19 (1H, dd, J 10.7 and J 6.8 Hz), 2.92 (1H, m), 2.67 (1H, dd, J 14.1 and J 5.8 Hz), 2.47 (1H, dd, J 14.3 and J 7.5 Hz). No exchangeable protons were observed. LCMS (ES+) 208.0 (M)+, RT 1.30 minutes (Method 1).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.[H][H]>[Pd].C(OCC)(=O)C>[F:1][C:2]1[C:3]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CC1(C)OB(c2cccc([N+](=O)[O-])c2F)OC1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cccc(N)c2F)OC1(C)C

Procedure:
A mixture of Intermediate 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg), 10% palladium on carbon (50 mg) and ethyl acetate (20 ml) was stirred under 1 atmosphere of hydrogen for 16 h. The mixture was sparged with nitrogen and filtered. The filtrate was concentrated to provide the title compound, which was used without further purification. MS m/z 237.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:10]([C:24](=[O:29])NCOC)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]1[CH:32]=[CH:33][C:34]2[O:38][CH:37]=[CH:36][C:35]=2[CH:39]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:10]([C:24]([C:37]2[O:38][C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:39][C:35]=3[CH:36]=2)=[O:29])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCNC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reactant: Fc1ccc2occc2c1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)c2cc3cc(F)ccc3o2)C1

Procedure:
The title compound was prepared from (RS)-2-(methoxymethylcarbamoyl)piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (1.25 g, 3.07 mmol) (WO01/00214) and 5-fluorobenzofuran (0.42 g, 3.09 mmol) (WO99/51575) by the method of Description 2 as a pale green gum (0.81 g, 55%).
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.N[C:11]1[C:12]([Cl:24])=[C:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:14]([Cl:18])=[CH:15][C:16]=1[Cl:17].[Cu][C:26]#[N:27].[C-]#N.[K+].Cl>N.C(OCC)(=O)C.C(O)(=O)C>[C:26]([C:11]1[C:12]([Cl:24])=[C:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:14]([Cl:18])=[CH:15][C:16]=1[Cl:17])#[N:27]
Reactant: Nc1c(Cl)cc(Cl)c(CCC(=O)O)c1Cl
Reactant: N#C[Cu]
Agent: Cl
Agent: N
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#Cc1c(Cl)cc(Cl)c(CCC(=O)O)c1Cl
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
7 g of sodium nitrite is introduced under agitation at +5° C. into 84 ml of concentrated sulfuric acid. The mixture is stirred for another 10 minutes and then heated to 70° C. to obtain a clear solution. After cooling to 5° C., 42 ml of glacial acetic acid is added thereto under ice bath cooling. Then, 21.5 g of 3-(3-amino-2,4,6-trichlorophenyl)propionic acid is added in incremental portions at between 0° C. and +5° C., and the mixture is stirred for 2 hours at 5° C. The mixture is poured on 200 g of ice and thereafter, under agitation, is introduced into a solution of 35.4 g of copper(I) cyanide and 66.8 g of potassium cyanide in 900 ml of semiconcentrated ammonia; during this step, nitrogen is liberated. After stirring overnight at room temperature, 800 ml of ethyl acetate is added and the mixture is brought to pH 1 by dropwise addition of concentrated hydrochloric acid. After separating the precipitated inorganic salts by vacuum-filtering, the ethyl acetate phase is removed, washed twice with respectively 300 ml of water, and evaporated to dryness after drying over sodium sulfate. Recrystallization from seven times the amount of toluene yields 16 g (72% of theory) of 3-(3-cyano-2,4,6 -trichlorophenyl)propionic acid as a white powder, mp 127°-129° C.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([NH:24][C:25]1[C:28]2([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:27](=[O:34])[C:26]=1[Cl:35])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([C:17]1[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:16])[CH2:10][CH2:9]2.ClC1C=NC=C(Cl)C=1C(N1C2C(=CC(CC(NC3C4(CCCCC4)C(=O)C=3)C(O)=O)=CC=2)CC1)=O>>[Cl:35][C:26]1[C:27](=[O:34])[C:28]2([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:25]=1[NH:24][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([C:17]1[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:16])[CH2:10][CH2:9]2)[C:3]([OH:36])=[O:2]
Reactant: COC(=O)C(Cc1ccc2c(c1)CCN2C(=O)c1cccnc1Cl)NC1=C(Cl)C(=O)C12CCCCC2
Agent: O=C(O)C(Cc1ccc2c(c1)CCN2C(=O)c1c(Cl)cncc1Cl)NC1=CC(=O)C12CCCCC2
Product: O=C(O)C(Cc1ccc2c(c1)CCN2C(=O)c1cccnc1Cl)NC1=C(Cl)C(=O)C12CCCCC2

Procedure:
The title compound was prepared from the compound of Example 14 in a similar manner to the compound of Example 2 as a white lyophilised powder (98%). δH NMR (d6 DMSO), 8.75 (0.8H, d, J 9.3 Hz), 8.60 (0.2H, dd, J 4.8 and 1.9 Hz), 8.53 (0.8H, dd, J 4.8 and 1.9 Hz), 8.05 (2H, m), 7.59 (1H, m), 7.18 (1.8H, m), 6.73 (0.2H, d, J 8.5 Hz), 5.51 (0.2H, d, J 8.8 Hz), 4.58 (0.8H, m), 4.49 (0.2H, m), 4.22 (0.4H, m), 3.78 (1.6H, t, J 8.4 Hz), 3.21 (1H, dd, J 13.8 and 4.3 Hz), 3.08 (2H, m), 2.96 (0.8H, dd, J 13.8 and 9.9 Hz), 2.84 (0.2H, m), 1.45 (10H, br m); m/z (ES+, 70 eV) 514 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[O:21][Si](C(C)C)(C(C)C)C(C)C)[N:10]([C:32]([C:34]3[C:39]([F:40])=[CH:38][C:37]([F:41])=[CH:36][C:35]=3[F:42])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.Br[CH2:67][C:68]([NH2:70])=[O:69]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[O:21][CH2:67][C:68]([NH2:70])=[O:69])[N:10]([C:32](=[O:33])[C:34]3[C:35]([F:42])=[CH:36][C:37]([F:41])=[CH:38][C:39]=3[F:40])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: NC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cccc(C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1OCC(N)=O

Procedure:
To [5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone (32.3 μmol) is added tetrabutylammonium fluoride in tetrahydrofuran (1 M) (48.5 μmol). The mixture is stirred for an hour and 2-bromo-acetamide (48.5 μmol) is added. The mixture is stirred at room temperature for 12 hours. After evaporation of the solvent the residue is purified by preparative LC/MS (20-100% MeCN/H2O) to give 2-{2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-6-methoxy-phenoxy}-acetamide: 1H NMR (400 MHz, CDCl3): δ 7.63-7.62 (m, 2H), 7.57 (s, 1H), 7.22-7.12 (m, 3H), 7.02 (dd, J1=8.4 Hz, J2=2 Hz, 2H), 6.9 (bs, 1H), 6.85 (t, J=8.4 Hz, 2H), 6.10 (s, 1H), 4.83 (d, J=15.2 Hz, 1H), 4.68 (d, J=15.2 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[C:20]([CH3:35])=[N:21][N:22]4[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1)=[CH2:5])C.Cl.O1CCOCC1>C(Cl)Cl>[C:4]([C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[C:20]([CH3:35])=[N:21][N:22]4[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1)(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)c1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
A solution of 7-(1-ethoxyvinyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (56.4 mg, 0.121 mmol) in DCM (1 mL) was treated at ambient temperature with a 4.0 M solution of HCl in dioxane (10 equivalents). The reaction mixture was stirred at ambient temperature for 0.5 hours, then quenched with saturated aqueous sodium bicarbonate. The resulting suspension was extracted with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative thin-layer chromatography (silica, 5% MeOH/DCM as eluent) to afford 24 mg of desired product as a solid. MS (ES+APCI) m/z=439 (M+H) detected.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[C:4]([O:13][CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][NH:22]2)=[CH:18][C:17]=1B1OCC(C)(C)CO1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1.O.C(O)C>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][NH:22]2)=[CH:18][C:17]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(C)(C)CO
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C(C)(C)CO)c(OC)c3)cc12
Temperature: 115 °C
Reaction time: 2.5 h
Yield: 56 %

Procedure:
A mixture of 2-(4-bromo-2-methoxyphenyl)-2-methylpropan-1-ol (crude product from Step 4, containing 40% of the desired material, 75 mg, 0.12 mmol), methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (45 mg, 0.14 mmol), PdCl2(dppf) (11 mg, 0.013 mmol), potassium carbonate (80 mg, 0.58 mmol), toluene (0.6 mL), ethanol (0.3 mL), water (0.3 mL), and THF (0.3 mL) was stirred at 115° C. for 2.5 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (4 mL) of ethyl acetate. The extract was loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 10% to 40% of ethyl acetate in heptane gave the title compound (25 mg, 56% yield). MS (ES−) 386.2 (M−H)−. Retention time: 3.38 min. Column: Phenomenex Gemini-NX, 4.6 mm×50 mm, C18, 3 μm, 110A; Column Temperature 60° C. Mobile Phase A: 0.1% formic acid in water (v/v); Mobile Phase B: 0.1% formic acid in acetonitrile (v/v) Gradient Profile: Flow-1.5 mL/min. Initial conditions: A-95%, B-5%; Linear Ramp to A-0%, B-100% over 0.0-4.10 min; hold at A-0%, B-100% from 4.10-4.50 min; return to initial conditions 4.60-5.0 min.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17]([CH2:19][S:20][CH3:21])=[O:18]>C1COCC1.CO.ClCCl>[CH3:16][S:17]([C:19]([S:20][CH3:21])=[CH:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: O=Cc1cnccc1Oc1ccccc1
Reactant: CSCS(C)=O
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CSC(=Cc1cnccc1Oc1ccccc1)S(C)=O
Yield: 12.1 %

Procedure:
To a stirred solution of 4-phenoxy-3-pyridinecarboxaldehyde (0.687 g, 3.45 mmol) and methyl methylsulphinylmethyl sulphide (0.429 g, 3.45 mmol) in THF was added dropwise Triton B (0.53 ml, 40% solution in methanol). The mixture was heated at reflux for 2 hours, allowed to cool and then diluted with dichloromethane (150 ml). The solution was washed with saturated brine (2×) and the solvent was evaporated. Flash chromatography (eluent ether-ethyl acetate) of the resulting residue gave 3-(2'-methylsulphinyl-2'-methylthiovinyl)-4-phenoxypyridine as a pale yellow gum (0.128 g); 1H NMR delta (CDCl3) 2.32 (3H,s), 2.77 (3H,s), 6.60 (1H,d), 6.9-7.5 (5H,m), 7.93 (1H,s), 8.32 (1H,d), 9.10 (1H,s).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:15][C:14]([NH:16][C:17](=[O:32])[CH2:18][C:19]2[N:20]=[C:21]([NH:24]C(=O)OC(C)(C)C)[S:22][CH:23]=2)=[N:13][CH:12]=1)([CH3:10])[CH3:9].C1(OC)C=CC=CC=1>C(Cl)Cl>[NH2:24][C:21]1[S:22][CH:23]=[C:19]([CH2:18][C:17]([NH:16][C:14]2[S:15][C:11]([CH:8]([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[O:32])[N:20]=1
Reactant: CC(C)c1cnc(NC(=O)Cc2csc(NC(=O)OC(C)(C)C)n2)s1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cnc(NC(=O)Cc2csc(N)n2)s1

Procedure:
Trifluoroacetic acid (168 ml) was added to a solution of tert-butyl 4-{2-[(5-isopropyl-1,3-thiazol-2-yl)amino]-2-oxoethyl)-1,3-thiazol-2-ylcarbamate (22 g, 57.51 mmol) in CH2Cl2 (750 ml) and anisole (9.33 ml, 86.27 mmol) under ice-cooling.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[CH2:7][CH2:8][CH:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:33]=[C:32]([C:34]([NH:36][C:37]4[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=4[F:44])=[O:35])[CH:31]=[CH:30][C:29]=3[F:45])[CH:24]=[CH:23][N:22]=2)[NH:18][CH:17]=1)=[O:15])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].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.[CH2:80]([NH2:82])[CH3:81].Cl>O1CCCC1.O>[CH2:80]([NH:82][C:10](=[O:11])[CH:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:33]=[C:32]([C:34]([NH:36][C:37]4[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=4[F:44])=[O:35])[CH:31]=[CH:30][C:29]=3[F:45])[CH:24]=[CH:23][N:22]=2)[NH:18][CH:17]=1)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:46])[CH3:81]
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)O)c[nH]4)c3)c2)c1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 5-tert-butoxy-2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-oxopentanoic acid (150 mg, 0.24 mmol) in 10 ml of anhydrous tetrahydrofuran were added HATU (109 mg, 0.29 mmol) and N,N-diisopropylethylamine (93 mg, 0.72 mmol). The mixture was heated at 60° C. for 15 minutes and cooled to room temperature, followed by addition of 2M ethylamine solution in THF (0.18 ml, 0.36 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% methanol in chloroform to give tert-butyl 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-oxopentanoate as white solid. Yield: 100 mg, 64%.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:47]=[CH:46][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[N:20]([C:28](=[O:41])[CH2:29][N:30]3[C:34](=[O:35])[C:33]4=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]4[C:31]3=[O:40])[C:19]3[CH:42]=[CH:43][CH:44]=[CH:45][C:18]2=3)=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.[BrH:48].C(O)(=O)C>C(Cl)(Cl)Cl>[BrH:48].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[N:20]([C:28](=[O:41])[CH2:29][N:30]3[C:31](=[O:40])[C:32]4=[CH:39][CH:38]=[CH:37][CH:36]=[C:33]4[C:34]3=[O:35])[C:19]3[CH:42]=[CH:43][CH:44]=[CH:45][C:18]2=3)=[CH:46][CH:47]=1
Reactant: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1)OCc1ccccc1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 92 %

Procedure:
To a solution of (3aR*,10aS*)-9-[4-(benzyloxycarbonylamino)benzyl]-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (366 mg, 0.58 mmol) in chloroform (3 mL) was added 25% hydrogen bromide/acetic acid (1 mL) and the mixture was stirred at room temperature for 75 minutes. This reaction mixture was concentrated under reduced pressure and the residue was crystallized from ethanoldiethyl ether to provide 309 mg (yield 92%) of the title compound. m.p. 222°-224° C.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][NH:6][CH2:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:27]([CH3:39])[CH:26]=3)([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:16]=2)[CH:11]=1)=[O:9])C.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:37][C:34]([CH3:35])([CH3:36])[C:33](=[O:38])[CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:20]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([C:8]([CH2:7][NH:6][CH2:5][C:4]([OH:40])=[O:3])=[O:9])[CH:19]=[CH:18]3)([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:26][C:27]=1[CH3:39]
Reactant: CCOC(=O)CNCC(=O)c1ccc2cc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)CNCC(=O)O)ccc2c1
Temperature: 50 °C
Yield: 84.5 %

Procedure:
Treat a solution of [(6-{1-[4-(3,3-Dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carbonyl)methylamino]acetic acid ethyl ester (0.090 g, 0.16 mmol) in THF (1.25 mL) and EtOH (2.5 mL) with 2N NaOH (0.80 mL, 1.6 mmol). Heat the mixture to 50° C. for 16 h. Acidify the reaction mixture to pH 1 using 1N HCl. Concentrate the resulting mixture. Dilute the residue with EtOAc and water (25 mL each). Separate and discard the aqueous layer. Wash the organic layer with brine, dry over Na2SO4, and filter. Concentrated the filtrate to give the title compound as a white solid (0.070 g, 85%). MS (ES) m/e 518 (M+1).