Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([Sn](Cl)(Cl)CCCC)[CH2:28]CC.C(=O)C.C1([SiH3])C=CC=CC=1>C1COCC1>[CH2:27]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=1)=[O:16])[CH3:28]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2Nc2ccccc2)cc1
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Agent: CC=O
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: CCN(c1ccccc1)c1ccccc1NC(=O)c1ccc(C(=O)OC)cc1
Reaction time: 0.25 h
Yield: 530 %

Procedure:
To a stirring solution of compound 112 (1.00 g, 2.89 mmol) in THF was added dibutyltin dichloride (0.175 g, 0.577 mmol) and acetaldehyde (1.182 g, 26.8 mmol) and the reaction mixture was stirred 15 minutes. Phenylsilane (0.375 g, 3.46 mmol) was added and the reaction mixture was stirred at room temperature 60 h then solvent evaporated. The resulting crude product was purified by Isco (80 g column, 10%-50%) to afford title compound 113 (1.145 g, 100%) as a yellowish oil. LRMS (ESI): (calc) 374.16 (found) 375.4 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[CH:14]=[CH:13][N:12]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.[NH2:30][C@@H:31]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][C:33]([OH:35])=[O:34].C([O-])([O-])=O.[Na+].[Na+].Cl>C1COCC1.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:30][C@@H:31]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][C:33]([OH:35])=[O:34])[CH:14]=[CH:13][N:12]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)[C@H](N)CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(S(C)=O)n3)c3cc(F)cnc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(N[C@H](CC(=O)O)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Temperature: 125 °C
Yield: 31 %

Procedure:
A mixture of 5-fluoro-3-(4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 127a, (0.052 g, 0.121 mmol) and (3R)-3-amino-4,4-dimethyl-pentanoic acid, 2a, (0.035 g, 0.242 mmol) along with Na2CO3 (0.051 g, 0.483 mmol) in a mixture of THF (0.780 mL) and acetonitrile (0.260 mL) was heated to 125° C. for 30 minutes under microwave irradiation. Then, the temperature was raised to 150° C. for a further 2.5 hours. The mixture was neutralized with aqueous 2N HCl and extracted with several portions of EtOAc. The organic solvents were evaporated in vacuo. Purification by flash chromatography (SiO2, 0-100% hexanes-EtOAc (with 10% MeOH)) provided 19 mg of the desired material (31% yield), which was used in the next step without further purification: LCMS Gradient 10-90%, 0.1% trifluoroacetic acid, 5 minutes, C18/ACN, RT=2.70 minutes (M+H) 512.00.
Reaction SMILES: ClC1C([C:12]2[C:13](F)=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[NH:17][C:16]=3[CH:22]=2)=NN(C)C=1C(F)(F)F.C([O-])([O-])=O.[K+].[K+].C(Br)C#C>CC(C)=O.O>[O:20]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:22][C:16]=2[NH:17][C:18](=[O:21])[CH2:19]1
Reactant: Cn1nc(-c2cc3c(cc2F)OCC(=O)N3)c(Cl)c1C(F)(F)F
Agent: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1COc2ccccc2N1
Temperature: 40 °C
Reaction time: 6 h
Yield: 231.5 %

Procedure:
At 25° C., 3.0 g (8.6 mmole) of the product of step A, 1.22 g (6.0 mmole) K2CO3 and 0.79 mL (8.8 mmole) 80% propargyl bromide were slurried in 50 mL acetone. The reaction was stirred at 40° C. for 6 hours. The reaction was cooled, diluted with 100 mL cold water, and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and stripped in vacuo. The residue was recrystallized from methylcyclohexane to give 2.97 g (89%) of 2H-1,4-benzoxazin-3(4H)-one, 6-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-4(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one as a beige solid, mp 142°-143° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21]>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]([OH:21])[CH2:7][C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Cc1cc(C)on1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CC(O)c2cccc(Cl)c2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dimethylisoxazole (104 g, 1.07 mol, 1 eq) in THF (1 L) cooled to −78° C. under nitrogen, a solution of lithiumdiisopropylamide (1.8M ethylbenzene in THF) (630 mL, 1.134 mol, 1.06 eq) was added dropwise. After 1 hr, a solution of 3-chlorobenzaldehyde 100 g, 0.711 mole, 0.66 eq) in THF (300 mL) was added drop wise at −78° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. It was cooled to 0° C., and quenched by saturated ammonium chloride solution (130 mL). The organic layer was concentrated to dryness. Water (1 L) was added to the residue was extracted with ethyl acetate (2×1 L). Combined organic extracts were washed with brine (700 mL) dried over anhydrous sodium sulfate. Concentrated and purified by column chromatography (50% ethyl acetate in hexane) over silica gel using a mixture of ethyl acetate and hexanes as eluant. The title compound was obtained as viscous brown oil (120 g, 0.507 mol, 48%).
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[CH:19]12[O:27][CH:23]([CH2:24][NH:25][CH2:26]1)[CH2:22][N:21]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1)[CH2:20]2>CN(C=O)C>[C:36]([C:35]1[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:21]2[CH2:22][CH:23]3[O:27][CH:19]([CH2:26][N:25]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:24]3)[CH2:20]2)=[CH:39][CH:38]=1)#[N:37]
Reactant: N#Cc1ccc(CCCCN2CC3CNCC(C2)O3)cc1
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCN1CC2CN(CCCCc3ccc(C#N)cc3)CC(C1)O2
Temperature: 54 °C
Reaction time: 24 h

Procedure:
Triethylamine (2.2 mL, 0.016 mol) and tert-butyl 2-bromoethylcarbamate (see Preparation R above, 2.83 g, 0.013 mol) were added to a solution of 4-[4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]benzonitrile (see Preparation G above, 3.0 g, 0.011 mol) in DMF (50 mL). The mixture was stirred for 24 h at 54° C., cooled to 25° C., and concentrated in vacuo. The residue was dissolved in chloroform and washed with saturated sodium chloride. The aqueous layer was separated and extracted with chloroform (2×150 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting material was chromatographed on silica gel, eluting first with chloroform:acetonitrile:conc. ammonium hydroxide (9:1:0.02) until the higher Rf impurities were removed. Then the eluent was switched to chloroform:methanol:conc. ammonium hydroxide (9:1:0.02). This afforded 2.76 g (61%) of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:25]([CH2:26][CH2:27][CH3:28])[C:24]([CH2:29][CH2:30][O:31][CH3:32])=[N:23][C:17]=3[C:18]([NH2:22])=[N:19][C:20]=2[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:22][C:18]1[C:17]2[N:23]=[C:24]([CH2:29][CH2:30][O:31][CH3:32])[N:25]([CH2:26][CH2:27][CH3:28])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:21][C:20]=2[N:19]=1
Reactant: CCCn1c(CCOC)nc2c(N)nc3cc(OCCCN)ccc3c21
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OCCCNC(=O)C(C)C)ccc3c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
Isobutyryl chloride (0.375 nL, 3.58 mmol) was added dropwise to a slurry of 7-(3-aminopropoxy)-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 394, 1.28 g, 3.58 mmol) in dichloromethane (22 mL) at 0° C. The reaction mixture was allowed to stir for 30 minutes at 0° C., then the reaction mixture was allowed to stir for 16 hours at ambient temperature. Saturated aqueous sodium carbonate was added and the reaction mixture was stirred for 1 hour, resulting in the formation of a flocculent solid. The solid was isolated by filtration and dissolved in dichloromethane. The dichloromethane was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting white solid was recrystallized from acetonitrile to afford 1.14 g of N-(3-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-methylpropanamide as an off-white solid.
Reaction SMILES: O[C:2]1([C:30]([F:33])([F:32])[F:31])[CH:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:8]2[CH2:19][NH:20][CH:21](C(OC(C)(C)C)=O)[CH2:22][N:6]3[C:7]2=[C:3]1[CH:4]=[CH:5]3.C(Cl)Cl.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[CH2:11]([C:10]1([OH:40])[CH:9]=[C:8]2[CH2:19][NH:20][CH2:21][CH2:22][N:6]3[C:7]2=[C:3]([CH:4]=[CH:5]3)[CH:2]1[C:30]([F:31])([F:32])[F:33])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)C1Cn2ccc3c2C(=CC(CCc2ccccc2)C3(O)C(F)(F)F)CN1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(CCc2ccccc2)C=C2CNCCn3ccc(c32)C1C(F)(F)F

Procedure:
The Boc group was removed from tert-butyl 7-hydroxy-6-phenethyl-7-(trifluoromethyl)-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxylate (138 mg, 0.3 mmol) (prepared as in Example 2 above) under standard conditions (CH2Cl2/trifluoroacetic acid) yielded 6-phenethyl-7-(trifluoromethyl)-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indol-6-ol trifluoroacetate, which was dissolved in THF (5 mL) and the resulting mixture was cooled to 0° C. Triethylamine (3.75 eq) was added, followed by addition of isopropyl isocyanate (1.7 eq). The resulting mixture was stirred at 0° C. for 30 min, then warmed to room temperature and stirred overnight. The resulting mixture was concentrated, dissolved in ethyl acetate (20 mL), and washed sequentially with water, NaHCO3 (sat. aq.) and brine, then dried (Na2SO4) and concentrated to yield 7-hydroxy-N-isopropyl-6-phenethyl-7-(trifluoromethyl)-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxamide (134 mg, MH+=448).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(C)(C)C(=O)N(Br)C1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.CC1C=CC=C([N+]([O-])=O)C=1C([O-])=O>C(OC)(=O)C>[Br:15][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)[O-]
Solvent: COC(C)=O
Product: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Temperature: 16.5 °C
Reaction time: 0.92 h

Procedure:
A mixture of methyl 2-methyl-6-nitrobenzoate (200.0 g, 1.02 moles, previously prepared), 1,3-dibromo-5,5-dimethylhydantoin (DBH, 162.0 g, 0.57 mole, from Aldrich Chemicals) and methyl acetate (1.20 L, from Aldrich Chemicals) was charged into a 3-L three-necked flask at about 20-25° C. under nitrogen. After the reaction mixture was refluxed for 0.5-1 hour, a solution of 2,2′-azobisisobutyronitrile (AIBN, 8.6 g, 52 mmol, from Aldrich Chemicals) in 100 mL of methyl acetate was charged over 15-30 minutes. The reaction mixture was refluxed for 6.5-8 hours until the amount of unreacted 2-methyl-6-nitrobenzoate was less than 5-10%. The reaction mixture was cooled to 15-18° C. and kept at 15-18° C. for 50-60 minutes. The solid was filtered, washed with cold (i.e., 5-10° C.) methyl acetate (2×100 mL) until there was less than 3% of methyl 2-bromomethyl-6-nitrobenzoate remained in the solid. Next, after heptane (1.00 L) was charged into the filtrate, the upper layer organic phase was washed with 2% of brine (2×500 mL) and deionized water (1-2×500 mL) until there was less than 0.5% (area percentage at 210 nm) of unreacted 5,5-dimethylhydantoin according to measurement by HPLC. After the solution was concentrated under a reduced pressure to remove about 1.80-1.90 L of methyl acetate, methyl tert-butyl ether (MTBE, 300 mL) was charged. After the reaction mixture was refluxed at 65-70° C. for 10-15 minutes, the solution was cooled to 50-55° C. over 0.5-1 hour and seeded with 500 mg of methyl 2-bromomethyl-6-nitrobenzoate at 45-50° C. The suspension was cooled to 20-25° C. and kept at 20-25° C. for 2-3 hours. The solids were collected by filtration, washed with 5-10° C. a cold mixture of heptane and MTBE in a volume ratio of 1:2 (2×100 mL), and dried to a constant weight at 20-25° C. under a vacuum at 100-120 ton. The yield of methyl 2-bromomethyl-6-nitrobenzoate was 185.2 g (66%), based on 200.0 g input of methyl 2-methyl-6-nitrobenzoate. The product was found to have a purity of >98% measured by HPLC based on area percentage, and a water content of <0.1% measured by Karl Fisher titration.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([OH:21])=O)[CH:13]=[CH:12]2)(=[O:7])[CH3:6]>CN(C)C=O>[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([Cl:3])=[O:21])[CH:13]=[CH:12]2)(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2cc(C(=O)Cl)ccc2c1

Procedure:
2.0 ml of thionyl chloride and a drop of N,N-dimethylformamide were added to 1.45 g (6.30 mM) of 6-acetoxy-2-naphthoic acid, followed by refluxing for 30 minutes under stirring. Excessive thionyl chloride was distilled off from the above mixture under reduced pressure to obtain 6-acetoxy-2-naphthoyl chloride. ##STR32##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[N:12]([OH:13])[C:11]([C:14]([F:17])([F:16])[F:15])=[N:10][C:7]2=[N:8][CH:9]=1)([O-])=O.C(O)C.Cl.[H][H]>[Pd].O>[NH2:1][C:4]1[CH:5]=[C:6]2[N:12]([OH:13])[C:11]([C:14]([F:15])([F:17])[F:16])=[N:10][C:7]2=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnc2nc(C(F)(F)F)n(O)c2c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cnc2nc(C(F)(F)F)n(O)c2c1

Procedure:
6-Nitro-1-hydroxy-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (4.9 grams) was mixed with 100 milliliters of ethanol and 3 milliliters of concentrated hydrochloric acid, and 1 gram of 5 percent palladium on carbon was added to the mixture. The mixture was hydrogenated to a 3 mole-equivalent uptake of hydrogen. The reaction mixture was then filtered and evaporated, yielding a gummy solid residue which was taken up in 150 milliliters of water and used directly in the reaction reported in the following example.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:9]2[CH:20]=[C:19]([CH:21]([N:23]([CH3:34])[S:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH3:22])[CH:18]=[CH:17][C:10]=2[O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:6]=[CH:7][CH:8]=1.[OH-].[Li+]>CO.O>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C:9]2[CH:20]=[C:19]([CH:21]([N:23]([CH3:34])[S:24]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH3:22])[CH:18]=[CH:17][C:10]=2[O:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)COc1ccc(C(C)N(C)S(=O)(=O)c2ccc(F)cc2)cc1-c1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(c1ccc(OCC(=O)O)c(-c2cccc(C(F)(F)F)c2)c1)N(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.2 %

Procedure:
To a solution of methyl 2-(2-(3-trifluoromethylphenyl)-4-(1-(4-fluoro-N-methylphenylsulfonamido)ethyl)phenoxy)acetate (19) in MeOH/H2O (4/1) was added lithium hydroxide (2 eq) and the mixture was stirred at room temperature for 2 h. After concentrating in vacuo, the residue was purified via semi-preparative HPLC to give 21.9 mg, (15.2% from Intermediate 18) of 2-(2-(3-trifluoromethylphenyl)-4-(1-(4-fluoro-N-methylphenylsulfonamido)ethyl)phenoxy)acetic acid (Example 22) as white solid. 1HNMR (CDCl3, 400 MHz): δ 7.61 (s, 1H), 7.53 (m, 3H), 7.31 (m, 1H), 7.25 (m, 1H), 7.22 (m, 1H), 7.03 (m, 2H), 6.72 (d, 1H), 5.01 (m, 1H), 4.14 (s, 2H), 2.38 (s, 3H), 1.06 (d, 3H). MS (ES-API): M=323.1 (main fragment). HPLC (Method B) tR=3.43 min.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[O:12][C:13]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:14]=2[N:15]=1>O>[N+:20]([C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:12][C:13]=2[CH:19]=1)([O-:22])=[O:21]
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2o1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Product: O=C(Nc1nc2ccc([N+](=O)[O-])cc2o1)c1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 87.5 %

Procedure:
Benzoyl chloride (1.17 mL, 10.0 mmol) was added to a suspension of 2-amino-6-nitrobenzoxazole (1.50 g, 8.37 mmol) in pyrdine (10 mL). After stirring for 24 h at 80° C., the solution was poured into water (250 mL). The mixture was stirred overnight at r.t. and the resulting precipitate was separated by filtration. N-(6-Nitrobenzoxazol-2-yl)benzamide (2.08 g, 7.32 mmol, 88%) was thus obtained as a yellow solid. LC/ESI-MS: /z =284 [M+H]+; m/z=282 [M−H]−; Rt=3.13 min.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][N:18]4[C:26]([C:29](=[O:34])C(Cl)(Cl)Cl)=[CH:27][CH:28]=[C:17]4[CH2:16]3)=[O:14])=[CH:9][C:8]=2[S:35]([NH2:38])(=[O:37])=[O:36])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1.O>O1CCOCC1>[OH2:4].[NH2:38][S:35]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:13]([N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][N:18]2[C:26]([C:29]([NH:39][CH2:40][C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[O:34])=[CH:27][CH:28]=[C:17]2[CH2:16]1)=[O:14])(=[O:37])=[O:36].[NH2:38][S:35]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:13]([N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][N:18]2[C:26]([C:29]([NH:39][CH2:40][C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[O:34])=[CH:27][CH:28]=[C:17]2[CH2:16]1)=[O:14])(=[O:37])=[O:36]
Reactant: NCc1cccnc1
Reactant: NS(=O)(=O)c1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1N1CCOCC1
Solvent: C1COCCO1
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1N1CCOCC1
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution containing 0.83 g (0.0014 mol) of 2-morpholin-4-yl-5-{[3-(trichloroacetyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}benzenesulfonamide of Step C and 0.30 g (0.0028 mol) of 3-aminomethylpyridine in 25 mL of 1,4-dioxane was stirred under reflux overnight. The reaction mixture was allowed to cool to room temperature and poured into 200 mL of water. The beige solid that precipitated was collected and washed with water to provide the title compound (0.35 g), m.p. 159-161° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([N:10]=[C:11]([O:18][CH3:19])[C:12]([O:16][CH3:17])=[N:13]2)=[C:8]([CH2:20]Br)[CH:7]=1.O>CN(C)C=O>[N:1]([CH2:20][C:8]1[CH:7]=[C:6]([Br:5])[CH:15]=[C:14]2[C:9]=1[NH:10][CH:11]([O:18][CH3:19])[CH:12]([O:16][CH3:17])[NH:13]2)=[N+:2]=[N-:3]
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1Nc2cc(Br)cc(CN=[N+]=[N-])c2NC1OC
Reaction time: 3 h

Procedure:
743 mg (2 equiv.) of sodium azide are added at 20° C. to 2.07 g (5.72 mmol) of 7-bromo-5-bromomethyl-2,3-dimethoxy-quinoxaline in 25 ml of dimethylformamide. After 3 hours, the mixture is poured into water, extracted with diethyl ether, washed with water and brine and dried with magnesium sulfate. The solvent is concentrated by evaporation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Br[C:22]1[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=[C:26]([Br:28])[N:27]=1.C(N(C(C)C)C(C)C)C>CC(O)C>[Br:28][C:26]1[N:27]=[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Br)nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)c1=O
Temperature: 100 °C
Reaction time: 15 h
Yield: 44.8 %

Procedure:
A mixture of 197b (500 mg, 1.8 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (530 mg, 2.0 mmol), N-ethyl-N-isopropylpropan-2-amine (1.5 mL, 0.90 mmol), and propan-2-ol (20 mL) was stirred at 100° C. for 15 h. After the reaction was completed, the solvent was removed under reduced pressure to afford 197c as a brown solid (375 mg, 45%). MS-ESI: [M+H]+ 465.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].[C:12]([O-])([O-])=O.[K+].[K+].O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:12]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(C)=O)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a stirred solution of 1-(3-methyl-4-hydroxylphenyl)ethanone (15.02 g, 100 mmol) in MeOH was added K2CO3 (41.5 g, 300 mmol), and Mel (28.4 g, 200 mmol). The reaction mixture was stirred at room temperature for 2 hours. Another 56.7 g of Mel was added, and the reaction mixture was stirred for an additional 2 hours. Water (50 ml) was added, and the product was extracted with 600 ml of EtOAc. The organic layer was washed with brine (250 ml), and dried with Na2SO4, and the solvent was removed in vacuo to give the title compound (10.2 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[OH:21][C:22]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([N:25]2[CH2:26][CH2:27][C:22]([OH:21])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:23][CH2:24]2)=[O:20])[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:8][N:9]=2
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Product: O=C(Cc1cc(Cl)cc2c(-c3ccccc3)onc12)N1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid with 4-hydroxy-4-phenyl-piperidine in an aprotic solvent and washing the reaction mixture with sodium bicarbonate solution.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.[C:17]([O:21][C:22](=[O:31])[NH:23][CH:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:5]1([O:4][C:2](=[O:3])[NH:30][CH:27]2[CH2:28][CH2:29][CH:24]([NH:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:31])[CH2:25][CH2:26]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)Oc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (1 eq.) is added dropwise to a solution of pyridine in DCM. The reaction mixture is cooled to 0° C. and a solution of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at RT for 1 hour. The reaction mixture is partitioned between (0.2 M) HCl(aq) and DCM. The organics are washed with water (×2), (sat)NaHCO3(aq) and brine. The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound.