Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[CH2:28](Cl)Cl.CCO[C:34]([CH3:36])=[O:35]>CCOC(C)=O.CO>[CH3:28][C:36]1[C:34](=[O:35])[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[C:6]([O:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:12][CH:11]=3)[C:7]=2[N:8]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)c2ccccc12
Reactant: CCOC(C)=O
Solvent: CO
Product: Cc1nc2c(Oc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)ccnc2[nH]c1=O

Procedure:
Method D2 was used with tert-butyl 4-(2,3-diaminopyridin-4-yloxy)naphthalen-1-ylcarbamate to afford a mixture of isomers. The residue was chromatographed (eluent: CH2Cl2/EtOAc: 6/1 towards 0/1 then EtOAc/MeOH:95/5) to afford at first tert-butyl 4-(2-methyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yloxy)naphthalen-1-ylcarbamate as a slightly yellow solid (401 mg, 0.958 mmol, 35%) and then tert-butyl 4-(3-methyl-2-oxo-1,2-dihydropyrido[2,3-b]pyrazin-8-yloxy)naphthalen-1-ylcarbamate as a yellow solid (607 mg, 1.45 mmol, 53%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20](Cl)[O:21][CH3:22].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:9]1[C:10]([N:20]([O:21][CH3:22])[CH3:19])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Reactant: CON(C)Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CC(C)(C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 23 h
Yield: 83.9 %

Procedure:
To a stirred solution of 1-tert-butyloxycarbonyl-4,4-dimethylpipecolic acid (24.6 g), N,O-dimethylhydroxylamino hydrochloride (12.12 g) and 1-hydroxybenzotriazole (18.09 g) in anhydrous dimethylformamide (400 ml) was added anhydrous triethylamine (30.7 ml) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.08 g) and the resulting mixture was stirred at room temperature for 23 hours under a nitrogen atmosphere. Diethyl ether (1 l) was added and the mixture was washed with 1N hydrochloric acid (2×250 ml), 1N sodium hydroxide (1×250 ml), brine (1×200 ml), dried (MgSO4) and concentrated. Flash chromatography (silica gel, hexane-diethyl ether, 40:60) of the residue afforded the title compound (24.1 g) as a white solid; δH (250 MHz, CDCl3) 4.76 (1H, br s), 3.92-3.74 (1H, m), 3.75 (3H, s), 3.58-3.42 (1H, m), 3.19 (3H, s), 1.84 (1H, dd, J=14.0 and 3.3 Hz), 1.64 (1H, dd, J=14.0 and 7.6 Hz), 1.52-1.34 (11H, m and s), 0.94 (3H, s), 0.92 (3H, s); m/z (CI)301 (M+ +1).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[Cl-].[C:19]([C:23]1[CH:32]=[CH:31][C:26]([CH:27]=[N+:28]([CH3:30])[CH3:29])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(C1C=CC(C=O)=CC=1)(C)(C)C.CNC>>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH:27]([N:28]([CH3:30])[CH3:29])[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:31][CH:32]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: C[N+](C)=Cc1ccc(C(C)(C)C)cc1
Reactant: CCn1c(-c2ccccc2)cc2ccccc21
Agent: CC(C)(C)c1ccc(C=O)cc1
Agent: CNC
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2ccc(C(C)(C)C)cc2)N(C)C)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-2-phenyl-1H-indole and (4-tert-butyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 4-tert-butylbenzaldehyde and dimethylamine.
Reaction SMILES: CON(C)[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])=[CH:16][C:15]=3[CH:27]=2)[CH:6]=1.[F:30][C:31]1[CH:32]=[C:33]([Mg]Br)[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[CH:12]=[CH:13][C:14]4[O:18][C:17]([CH2:19][CH2:20][N:21]5[CH2:25][CH2:24][CH2:23][C@H:22]5[CH3:26])=[CH:16][C:15]=4[CH:27]=3)[CH:6]=2)=[O:28])[CH:34]=[CH:35][CH:36]=1
Reactant: CON(C)C(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Reactant: Fc1cccc([Mg]Br)c1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(=O)c4cccc(F)c4)c3)ccc2o1
Yield: 46 %

Procedure:
The product from Example 145 and 3-fluorophenylmagnesium bromide were processed as described in Example 146 to provide the title compound (46% yield). MS (ESI APCI) m/z 428 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.17 (d, 3H), 1.36-1.53 (m, 1H), 1.72-1.86 (m, 2H), 1.94-2.07 (m, 1H), 2.22-2.33 (m, 1H), 2.39-2.58 (m, 2H), 2.93-3.14 (m, 2H), 3.18-3.3 (m, 2H), 6.62 (s, 1H), 7.37-7.45 (m, 1H), 7.49-7.52 (m, 2H), 7.52-7.66 (m, 4H), 7.72 (ddd, 1H), 7.77 (dd, 1H), 7.94 (ddd, 1H), 8.02 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:18][CH2:19][NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:18][CH2:19][NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])=[CH:10][CH:11]=1
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Reactant: CCOC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
A mixture of 4-(3,5-difluorophenoxy)phenol (0.50 g), ethyl N-2-chloroethylcarbamate (0.375 g), potassium carbonate (0.621 g) and anhydrous dimethylformamide (10 ml) was stirred at 100° C. for 3 hours, followed by cooling to room temperature. Ice-water (50 ml) was poured to the resultant mixture, which was extracted with toluene (50 ml). The toluene extract was washed with water and dried over anhydrous sodium sulfate. The toluene extract was concentrated under reduced pressure to give an oily residue. The residue was purified by silica gel column chromatography to give 0.605 g of ethyl N-2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate as a colorless liquid. nD25.5 1.5305.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([Cl:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:15])[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[N:7]=1
Reactant: CCOC(=O)Cc1c(Cl)nc(Cl)nc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1c(Cl)nc(Cl)nc1NCc1ccc(OC)cc1
Temperature: 60 °C
Yield: 45.5 %

Procedure:
To a solution of ethyl 2-(2,4,6-trichloropyrimidin-5-yl)acetate (43.3 g, 160.7 mmol) in N,N-dimethylformamide (500 mL) was added 4-Methoxybenzylamine (24.2 g, 176.8 mmol) and N,N′-diisopropylethylamine (24.9 g, 192.9 mmol), the reaction mixture was heated to 60° C. for 1 h. Quenched with water, extracted with ethyl acetate, and the organic extracts were combined, washed with hydrochloride (1 N), brine, dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography to afford the as a pale-yellow solid (27.1 g, yield 45.6%). 1H NMR (400 MHz, CDCl3) δ ppm 7.29 (dd, J=6.0, 3.9 Hz, 1H), 6.93-6.85 (m, 1H), 6.14 (s, 1H), 4.63 (d, J=5.3 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 3.62 (s, 2H), 1.23 (t, J=7.1 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8]([C:10]3[C:14]4[CH2:15][NH:16][CH2:17][CH2:18][C:13]=4[NH:12][N:11]=3)=[N:9][C:5]=2[CH:4]=1.[CH2:23]([N:25]([CH2:29][CH3:30])[C:26](Cl)=[O:27])[CH3:24]>>[CH2:23]([N:25]([CH2:29][CH3:30])[C:26]([N:16]1[CH2:17][CH2:18][C:13]2[NH:12][N:11]=[C:10]([C:8]3[NH:7][C:6]4[CH:19]=[CH:20][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][C:5]=4[N:9]=3)[C:14]=2[CH2:15]1)=[O:27])[CH3:24]
Reactant: CCN(CC)C(=O)Cl
Reactant: FC(F)(F)c1ccc2[nH]c(-c3n[nH]c4c3CNCC4)nc2c1
Product: CCN(CC)C(=O)N1CCc2[nH]nc(-c3nc4cc(C(F)(F)F)ccc4[nH]3)c2C1

Procedure:
By proceeding in a manner similar to Example 258(a) above but using 3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine [Example 251(d)] and diethylcarbamyl chloride there was prepared 3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide (103 mg) as a white solid. MS: 407.17 (M+H)+. HPLC (METHOD E1): RT=10.81 minutes.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[F:6][C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:6][C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.[Cl:5][CH2:4][CH2:3][CH2:2][N:16]1[CH2:15][CH2:14][N:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=2)[CH2:18][CH2:17]1
Reactant: ClCCCBr
Agent: Fc1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cccc(N2CCN(CCCCl)CC2)c1
Reaction time: 9 h

Procedure:
The 1-(3-chloropropyl)-4-(3-fluorophenyl piperazine used is prepared in the following manner: 32 g (203 m. moles) of 1-bromo-3-chloropropane are added drop by drop to a mixture of 12.2 g (67.7 m. moles) Of 1-(3-fluorophenyl piperazine [prepared according to D. R. Maxwell and W. R. Wragg, English Pat. No. 943,739, C.A. 60, 5522c (1964)], 9.4 g (68 m. moles) of potassium carbonate and 135 cc of N,N-dimethylformamide. The stirring is continued for 9 hours at ambient temperature. The inorganic products are then removed by filtration, then the filtrate is concentrated under reduced pressure. The residue is dissolved in ether, the solution washed with a saturated solution of sodium chloride, then dried on sodium sulfate. The evaporation of the ether supplies an oil which is distilled (boiling1 =137°-140°). The 1-(3-chloropropyl)-4-(3-fluorophenyl)piperazine is obtained in the form of an oil that is crystallized in hexane. Yield: 11.6 g (67%), Melting point=48°-49° C.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:16](=[O:23])[NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].O>ClCCl>[CH3:6][NH:7][C@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[O:23]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CN[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-Methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamic acid tert-butyl ester (3.45 g(9.57 mmol) was dissolved in dichloromethane (8 ml). The solution was cooled to 0° C. Trifluoroacetic acid (8 ml) was added. The reaction mixture was stirred for 45 min at 0° C. A saturated aqueous solution of sodium hydrogen carbonate (40 ml) was added. Solid sodium hydrogen carbonate was added until pH 7. Water (100 ml) was added, until a clear solution was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×30 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (180 g), using dichloromethane/methanol/25% aqueous ammonia as eluent to give 1.13 g of (2R)-2-methylamino-3-phenyl-N-(2,2,2-trifluoroethyl)propionamide.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[CH3:8][C:9]([CH3:13])([CH3:12])[CH2:10][NH2:11].[S-:14][C:15]#[N:16].[K+].O1CCOCCOCCOCCOCCOCC1.II>CCOC(C)=O.C(#N)C>[C:2]([C:3]1[S:14][C:15](=[NH:16])[N:11]([CH2:10][C:9]([CH3:13])([CH3:12])[CH3:8])[CH:4]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)CC=O
Reactant: N#C[S-]
Reactant: CC(C)(C)CN
Agent: C1COCCOCCOCCOCCOCCO1
Agent: II
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)Cn1cc(C(C)(C)C)sc1=N
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.8 %

Procedure:
To a solution of 3,3-dimethylbutanal (Aldrich) (3.99 g, 39.8 mmol) in of acetonitrile (40 mL) was added 4 g of molecular sieves (4A beads, 8-12 mesh) and 2,2-dimethylpropan-1-amine (Aldrich) (3.16 g, 36.2 mmol). The mixture was stirred for 12 h at room temperature. The mixture was filtered and to the filtrate was successively added potassium thiocyanate (4.68 g, 48.1 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (1.24 g, 4.71 mmol). The temperature was adjusted at 50° C. and the mixture was stirred until all solids were dissolved then iodine (18.4 g, 72.4 mmol) was added. The reaction was stirred at 50° C. for 12 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The solution was washed with a solution of sodium metabisulfate. The aqueous layers was brought to pH=9 by adding NaOH (25%) and extracted with EtOAc. The Organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was crystallized from EtOAc/Hexane to give 4.9 g of the title compound. MS (ESI+) m/z 227 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31]C6CCCCO6)[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl>CO.O1CCOCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([CH:23]5[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][OH:31])[CH2:27][CH2:28]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CCOC4CCCCO4)CC3)cc1OCC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CCO)CC3)cc1OCC2
Reaction time: 0.75 h
Yield: 30.5 %

Procedure:
A solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-piperidin-4-yl}-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (371 mg, 0.73 mmol) in methanol (3.5 mL) was treated with 4N HCl in dioxane (3.5 mL) and the mixture stirred for 45 min before being concentrated in vacuo. The resultant residue was re subjected to the reaction conditions as before and stirred for 1 h at RT before being concentrated in vacuo. The resultant residue was partitioned between DCM/saturated aqueous sodium hydrogen carbonate, the aqueous extracted twice with DCM and the combined organic extracts washed with brine and then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, column preconditioned with 1% TEA in DCM, gradient 0 to 7% methanol in DCM) to give 293 as a yellow foam (94 mg, 30%). LCMS: RT=2.61 min, [M+H]+=423. 1H NMR 400 MHz (DMSO-d) δ: 8.32 (1 H, d, J=8.28 Hz), 7.89 (2 H, d, J=1.96 Hz), 7.05 (1 H, dd, J=8.31, 1.76 Hz), 6.89 (1 H, d, J=1.71 Hz), 5.88-5.87 (1 H, m), 4.49 (4 H, q, J=5.91 Hz), 3.53 (2 H, t, J=7.21 Hz), 3.03 (2 H, d, J=11.27 Hz), 2.52 (3H, m), 2.16 (2 H, t, J=11.38 Hz), 1.76 (2 H, d, J=12.61 Hz), 1.67 (2 H, d, J=12.75 Hz), 1.47 (6 H, d, J=6.60 Hz)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.Cl[Si:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12]>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Si:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:3]=1
Reactant: Brc1cccc(Br)c1
Reactant: CC[Si](Cl)(CC)CC
Product: CC[Si](CC)(CC)c1cccc(Br)c1

Procedure:
1-Bromo-3-triethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing 1,3-dibromobenzene and chlorotriethylsilane as the ClSiR1R2 R3 compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([CH3:22])[NH:5][C:6]1[C:11]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.O.[C:25](OCC)(=[O:27])C>C(O)CO>[ClH:20].[OH:27][CH2:25][CH2:1][O:2][C:3](=[O:23])[C@@H:4]([CH3:22])[N:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[N:12]=[C:13]1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)[C@@H](C)Nc1ncccc1NC(=O)c1ccc(Cl)cc1
Solvent: OCCO
Solvent: O
Product: C[C@H](C(=O)OCCO)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Product: Cl
Temperature: 25 °C

Procedure:
A solution of (R)-N-[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]alanine methyl ester (42.5 g, 0.0127 mole) in ethylene glycol (250 ml) was refluxed under nitrogen for one hour. The solution was cooled to room temperature and approximately 5 ml of the solution was added to water. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted with two additional portions of ethyl acetate and the combined organic layers were washed three times with a saturated sodium chloride solution. The ethyl acetate layer was dried over sodium sulfate, filtered, and evaporated to a oil under reduced pressure. The oil was dissolved in isopropyl alcohol and was made acidic with hydrogen chloride/isopropyl alchol. Addition of isopropyl ether to the cloud point gave a solid. The solid was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at room temperature to give 0.25 g of title compound, mp 191°-195° C.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:34]=[CH:33][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C@@H:22]([CH3:32])[CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:20]=3)[C:15]([OH:17])=[O:16])=[C:9](Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CO.C1COCC1>[N:1]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C@@H:22]([CH3:32])[CH2:23][O:24][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[CH:20]=3)[C:15]([OH:17])=[O:16])=[CH:33][CH:34]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
3-[4-(Azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (3.08 g, 5.93 mmol) was dissolved in methanol (30 mL) and THF (30 mL). Triethylamine (2 mL) was added and the flask evacuated and purged with nitrogen (3 times). 10% Palladium on carbon (200 mg) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for 16 hours LC-MS showed only 26% required product. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off, and the flask containing the filtrate evacuated and purged with nitrogen (3 times). Fresh 10% Palladium on carbon (200 mg) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for a further 16 hours LC-MS showed complete reaction. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off, the filtrate concentrated in vacuo and dissolved in diethylether (50 mL), washed with water (20 mL), 1N citric acid (20 mL), saturated aqueous sodium chloride solution (20 mL) and dried (MgSO4) to give the title compound (2.16 g).
Reaction SMILES: COC1C=C[C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5]C=1.[O:31]1[CH:35]=CC(C=O)=[CH:32]1>>[O:31]1[CH:35]=[CH:5][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:32]1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1ccoc1
Product: O=C(NCCNCc1ccoc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 3-furaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 382 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (1H, br. s.) 10.25 (1H, s) 7.93-8.05 (2H, m) 7.75 (1H, d, J=5.37 Hz) 7.52 (1H, t, J=1.61 Hz) 7.46 (1H, d, J=0.68 Hz) 7.44 (1H, d, J=5.42 Hz) 7.28 (1H, dd, J=3.20, 2.66 Hz) 6.77 (1H, d, J=5.42 Hz) 6.38-6.43 (2H, m) 3.49 (2H, s) 3.30-3.35 (2H, m) 2.60 (2H, t, J=6.49 Hz)
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[OH:28])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:29][C:30](=[O:40])[C:31]2[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)=[C:4]([N+:41]([O-:43])=[O:42])[CH:3]=1.[CH2:44](O)[CH3:45].C(P(CCCC)CCCC)CCC.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH2:44][CH3:45])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:29][C:30](=[O:40])[C:31]2[CH:36]=[CH:35][C:34]([N:37]([CH3:38])[CH3:39])=[CH:33][CH:32]=2)=[C:4]([N+:41]([O-:43])=[O:42])[CH:3]=1
Reactant: CCO
Reactant: Cc1onc(-c2ccccc2O)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(N(C)C)cc3)c([N+](=O)[O-])cc2Cl)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(N(C)C)cc3)c([N+](=O)[O-])cc2Cl)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of N-(4-chloro-5-(4-(3-(2-hydroxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)-2-nitrophenyl)-4-(dimethylamino)benzamide (Example 117, 17 mg, 0.028 mmol), ethanol (2.461 μL, 0.042 mmol) and tri-n-butyl phosphine (10.40 μL, 0.042 mmol) in THF (2 mL) at 0° C. was added DIAD (8.19 μL, 0.042 mmol). The reaction mixture was stirred at 0° C. for 3 min. and at RT overnight.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][CH2:3]1.[C:18]1([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28](Br)[CH:27]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:11][C:10]([O:9][C:7]([NH:6][C@@H:5]([CH2:4][CH2:3][C:2](=[O:1])[C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:31]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:8])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Brc1cccc(OCc2ccccc2)c1
Product: COC(=O)[C@H](CCC(=O)c1cccc(OCc2ccccc2)c1)NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized (420 mg, 6%) following a similar procedure as set out earlier in Description 2 starting from 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D1, 3.69 g, 15.2 mmol) and 3-bromophenyl phenylmethyl ether (D39); Rt (HPLC): 6.2 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[SH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>CN(C=O)C.O>[OH:32][C:29]1[CH:30]=[CH:31][C:26]([S:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])=[CH:27][CH:28]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1cccs1
Temperature: 80 °C
Yield: 79.2 %

Procedure:
The product of Example 240a (1.50 g, 5.63 mmol) was dissolved in DMF to which K2CO3 (1.55 g, 11.27 mmol), and 4-mercapto-phenol (711 mg, 5.634 mmol) were added. The reaction mixture was then heated to 80° C. for 2 hrs. At this point the reaction mixture was cooled to room temperature and diluted with water which was then extracted with ethyl acetate to isolate the desired compound (1.66 g, 79%).