Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13].[OH-].[Na+]>C(O)(=O)C>[O:11]1[C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)NCc1ccc2c(c1)OCO2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a solution of 3,4-methylenedioxybenzylamine (10 g, 66.2 mmol) in acetic acid (50 mL) was added acetic anhydride (15.27 g, 150 mmol). The mixture was stirred at 20° C. for 30 minutes. Then it was adjusted to PH7 with 10% NaOH. The mixture was filtered to obtain a solid which was washed water and dried in vacuum to give N-(benzo[d][1,3]dioxol-5-ylmethyl)acetamide as a white solid (9.24 g, 77%). LC-MS: 194 [M+1]+; 1H-NMR (DMSO-d6): δ 1.84 (s, 3H), 4.12 (d, 2H, J=6.4 Hz), 5.98 (s, 2H), 6.71 (m, 2H), 6.83 (m, 2H), 8.28 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[C:20]([CH3:21])=[N:19][NH:18][C:7]=2[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[OH-:22].[Na+].Cl>C(O)(C)C>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]3[C:20]([CH3:21])=[N:19][N:18]([CH:7]4[CH2:6][CH2:5][CH2:10][CH2:9][O:22]4)[C:7]=3[N:8]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)nc2[nH]nc(C)c12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A mixture of 6-(4-hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methyl ester (10.9 g) and sodium hydroxide solution (1N, 80 mL) in isopropanol (80 mL) was stirred at r.t. for 90 min. The pH was adjusted to 3 with 1N HCl and the mixture was poured onto water. The precipitate formed was filtered off and dried in air to give 6-(4-Hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (10.2 g, 97% yield).
Reaction SMILES: C(OC(=O)NCCCN)(C)(C)C.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]1[N:23]=[C:24]([N:27]([CH2:35][CH2:36][CH2:37][NH:38]C(=O)OC(C)(C)C)[C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[O:29])[S:25][CH:26]=1.C(O)(C(F)(F)F)=O.ClCCl>>[NH2:38][CH2:37][CH2:36][CH2:35][N:27]([C:24]1[S:25][CH:26]=[C:22]([C:14]2[O:13][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH:15]=2)[N:23]=1)[C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)NCCCN(C(=O)c1cccs1)c1nc(-c2cc3ccccc3o2)cs1
Agent: CC(C)(C)OC(=O)NCCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCN(C(=O)c1cccs1)c1nc(-c2cc3ccccc3o2)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
According to the procedure in Example 19, (3-amino-propyl)carbamic acid tert-butyl ester was transformed into tert-butyl 3-(N-(4-(benzofuran-2-yl)thiazol-2-yl)thiophene-2-carboxamido)propylcarbamate, which was reacted with TFA/dichoromethane (3:2), stirred at room temperature for 30 min, concentrated in vacuo, then dissolved in MeOH and treated with 1M HCl/ether. The resulting precipitate was filtered and dried in vacuo to provide N-(3-aminopropyl)-N-(4-(benzofuran-2-yl)thiazol-2-yl)thiophene-2-carboxamide (220 mg) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]#[C:4][C:5](OCC)=[O:6].[CH3:11][NH:12][NH2:13]>C(Cl)Cl.C(OCC)(=O)C>[F:1][CH:2]([F:10])[C:3]1[N:12]([CH3:11])[N:13]=[C:5]([OH:6])[CH:4]=1
Reactant: CCOC(=O)C#CC(F)F
Reactant: CNN
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1nc(O)cc1C(F)F
Temperature: -78 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
10.2 g (0.068 mol) of ethyl 4,4-difluoro-2-butynoate in 20 ml of methylene chloride was added dropwise to a stirred solution of 4 ml (0.075 mol) of methylhydrazine in 80 ml of methylene chloride cooled to -78° C. The resultant reaction mixture was stirred overnight and subsequently concentrated in vacuo to afford 8.63 g of a clear, yellow oil. The oil was dissolved in ethyl acetate and washed with 10% aqueous sodium bicarbonate. The organic layer was dried, concentrated and recrystallized from carbon tetrachloride to give 2.2 g (21.7% yield) of a white crystalline solid, m.p. 115°-119° C.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)[CH:7]=[CH:6][C:5]=12.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:24][CH:23]=3)=[O:15])[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: O=C(O)c1cccnc1Oc1ccc2nsnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3nsnc3c2)cc1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
2-(Benzo[2,1,3]thiadiazol-5-yloxy)-nicotinic acid (30.8 mg, 0.11 mmol), 2-(4-aminomethyl-phenyl)-propan-2-ol (18.6 mg, 0.11 mmol), 1-hydroxybenzotriazole hydrate (16.8 mg, 0.12 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (25.9 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (10 ml) and stirred at room temperature over night. The solution was poured into water (30 ml) and extracted with ethyl acetate. The combined organic layers were washed successively with 1N NaOH, water, and brine, then dried over sodium sulfate and concentrated in vacuo. The resulting amber oil was purified by flash column chromatography (1:1 ethyl acetate/hexane) to afford a white foam (29 mg, 0.07 mmol).
Reaction SMILES: C[Al](C)C.[CH2:5]([N:7]1[C:12](=[O:13])[CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:9]=[C:8]1[CH2:20][C:21]([O:23]CC)=O)[CH3:6].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.S([O-])([O-])(=O)=O.[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH2:5]([N:7]1[C:12](=[O:13])[CH:11]=[C:10]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[N:9]=[C:8]1[CH2:20][C:21]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=1)=[O:23])[CH3:6]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1CC
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCn1c(CC(=O)Nc2ccc(F)cc2)nc(N2CCOCC2)cc1=O
Temperature: 80 °C

Procedure:
0.640 ml of a 2M solution of trimethylaluminium in toluene, and then, after stirring for 40 minutes at ambient temperature, a solution of 190 mg of ethyl [1-ethyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 6 ml of toluene are successively added, dropwise, to a solution of 0.13 ml of 4-fluoroaniline in 4 ml of toluene. The reaction mixture is heated at 80° C. for 4 hours, cooled using an ice bath and run into water. A 1M solution of potassium sulphate and ethyl acetate are then added, and the organic phase is extracted, washed again with a 1M solution of potassium phosphate and then dried over magnesium phosphate, filtered and, finally, concentrated under reduced pressure. After purification by silica column chromatography, eluent: 980101 then 960202 CH2Cl2/CH3CN/MeOH, 60 mg of 2-[1-ethyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(4-fluorophenyl)acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:15])=[C:10]([CH:14]=1)[C:11](Cl)=[O:12].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][CH:18]=1>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:15])=[C:10]([C:11]([C:25]2[S:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)=[CH:27][CH:26]=2)=[O:12])[CH:14]=1
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Reactant: Fc1ccc(-c2cccs2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccc(F)cc2)s1)c1cc(Br)ccc1Cl
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
AlCl3 (1.5 g, 11 mmol) was dissolved in 10 mL methylene chloride and cooled to −10° C., followed by addition of 5-bromo-2-chloro-benzoyl chloride 2a (2.54 g, 10 mmol) and 2-(4-fluorophenyl)thiophene 9b (1.78 g, 10 mmol). The reaction mixture was stirred for 30 minutes and then warmed to room temperature and stirred for another 16 hours. Thereafter, the reaction mixture was cooled to −10° C. The reaction mixture was extracted with ethyl acetate (50 mL×2) after a small amount of water and 20 mL 1 M hydrochloric acid were added. The organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound (5-bromo-2-chloro-phenyl)-[5-(4-fluorophenyl)-2-thienyl]methanone 9c (1.5 g, yellow solid), yield: 37.9%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)O1.[Cl:19][C:20]1[N:24]=[C:23](Cl)[S:22][N:21]=1.O.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[Cl:19][C:20]1[N:24]=[C:23]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[S:22][N:21]=1
Reactant: Clc1nsc(Cl)n1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Clc1nsc(-c2ccc3[nH]ccc3c2)n1
Temperature: 85 °C
Yield: 35.1 %

Procedure:
To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (2 g, 8.23 mmol, Aldrich) and 3,5-dichloro-1,2,4-thiadiazole (1.27 g, 8.23 mmol, Aldrich) in 1,2-dimethoxy ethane (30 mL)/H2O (10 mL) was added K2CO3 (2.27 g, 16.46 mmol) and Pd(PPh3)4 (0.95 g, 0.82 mmol). N2 gas was purged for 15 min through the mixture. The reaction was heated at reflux at 85° C. for 6 h. The mixture was cooled to RT and quenched with H2O (100 mL) and was extracted with EtOAc (2×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica-gel column chromatography (eluent: 5% EtOAc in petroleum ether) to give 3-chloro-5-(1H-indol-5-yl)-1,2,4-thiadiazole (680 mg, 35.5%) as an off white solid. MS (ESI, pos. ion) m/z: 236 (M+1); 1H-NMR (300 MHz, CDCl3): δ 8.5 (brs, 1H), 8.29 (d, J=0.8 Hz, 1H), 7.78 (dd, J=8.4, 1.8 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.32-7.31 (m, 1H), 6.67 (t, J=2.1 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1)([O-])=O.O.C1CCCCC=1.[ClH:26]>C(O)C.[Pd]>[ClH:26].[ClH:26].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1
Reactant: O=C(O)CCCCCNc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: C1=CCCCC1
Product: Nc1ccc(NCCCCCC(=O)O)cc1
Yield: 81 %

Procedure:
2 g (7.9 mmol) of 6-[N-(4-nitrophenyl)amino]caproic acid are partially dissolved in 40 ml of ethanol and 2 ml of water in a 150 ml three-necked flask equipped with a thermometer and a reflux condenser. 2 g of palladium-on-charcoal (10% active and 50% moisture) are then introduced, followed by 20 ml of cyclohexene. The mixture is brought to reflux for 2 hours and is then cooled, before being filtered through celite. After having run 4 ml (2.5 eq) of 5N hydrochloric acid onto the filtrate, the latter is evaporated to dryness and the residue is taken up in ethanol and precipitated from acetone. After filtration, 1.9 g of a white product are obtained, i.e. a final yield of 81%.
Reaction SMILES: [C:1]([O:7][C@H:8]1[C@H:20]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:19]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@H:18]([CH3:35])[O:17][C@@H:9]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1C=C(Cl)C=C(C(OO)=[O:44])C=1.CSC>C(Cl)Cl>[C:1]([O:7][C@H:8]1[C@H:20]([O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])[C@H:19]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@H:18]([CH3:35])[O:17][C@@H:9]1[S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:44])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CSC
Product: C[C@@H]1O[C@H](S(=O)c2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: -15 °C
Yield: 66.1 %

Procedure:
To a solution of phenyl 6-deoxy-2,3,4-tri-O-pivaloyl-1-thio-β-L-galactopyranoside 4 (2.47 g, 5.22 mmol) in 65 mL of CH2Cl2 at -78° C. is added mCPBA (1.53 g, 8.84 mmol). The reaction mixture is allowed to warm to -15° C. and then quenched with methyl sulfide (5.3 mL, 4.48 g, 17.4 mmol) and allowed to warm to room temperature. The reaction mixture is then diluted with 50 mL CH2Cl2, extracted with H2O (100 mL), saturated NaHCO3 (100 mL), saturated NaCl (100 mL), dried over Na2SO4, filtered and concentrated to afford a white solid. The sulfoxide is purified using flash chromatography (15% EtOAc/petroleum ether) to afford 1.81 g (66%) of 1,6-dideoxy-2,3,4-tri-O-pivaloyl-1-(phenylsulfinyl)-β-L-galactopyranose 5 as a mixture of diastereomers: Rf 0.05 and 0.13 (15% EtOAc/petroleum ether).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[F:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](Cl)=[O:23])=[CH:18][C:17]=1[CH3:27].[NH4+].[Cl-]>C1COCC1>[F:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([N:5]2[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]2=[O:9])=[O:23])=[CH:18][C:17]=1[CH3:27]
Reactant: Cc1cc(OCC(=O)Cl)ccc1F
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To the solution of (S)-( )-4-Isopropyl-2-oxazolidinone (992 mg, 5.6 mmol) in anhydrous 30 mL THF at −70° C. was slowly added n-BuLi (3.5 mL, 5.6 mmol, 1.6 M in hexane) over 15 minutes. The reaction mixture was stirred for 30 min at −70° C. and to it was slowly added a solution of 2-(4-fluoro-3-methylphenoxy)acetyl chloride crude solution in 4 mL THF. The resulting mixture was stirred at −70° C. for 2 h and the temperature was slowly raised over a period of 1 h. The mixture was poured into 30 mL saturated NH4Cl and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2×30 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the product isolated by Flash column chromatography eluting with 0% to 50% ethyl acetate/hexane to give 2.2 g of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24]>C(O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Solvent: CCO
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Reaction time: 0.01 h

Procedure:
All isomers of PGF2α were dissolved or diluted in adequate amount of ethanol and after aliquot, stored at −70° C. As an internal standard, 10 ng of 8-iso-PGF2α-d4 was mixed with 0.5 ml of plasma in a glass tube and was then purified by a C18 Solid-Phase Extraction column (J. T. Baker, MA, USA). Sample eluants were evaporated under a stream of nitrogen and re-dissolved in 50 μl acetonitrile:water (15:85 v/v) solution followed by vortex for 30 seconds and 10 μl extract was further analyzed with a LC/MS/MS system.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[C:22]1[N:27]=[C:26]([NH2:28])[C:25]([N+:29]([O-:31])=[O:30])=[C:24]([NH2:32])[N:23]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:22]3[N:23]=[C:24]([NH2:32])[C:25]([N+:29]([O-:31])=[O:30])=[C:26]([NH2:28])[N:27]=3)[N:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:5]2=[N:6][CH:7]=1
Reactant: Nc1nc(Cl)nc(N)c1[N+](=O)[O-]
Reactant: Fc1cnc2c(Cc3ccccc3F)n[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
156 mg (about 66% pure, 0.636 mmol) of the compound from example 6A were dissolved in DMF (3.5 ml), 28 mg (0.70 mmol) of sodium hydride (60% in mineral oil) were then added and the mixture was stirred at RT for 2 h. 115 mg (0.604 mmol) of 2-chloro-5-nitropyrimidine-4,6-diamine (synthesis: Helvetica Chimica Acta (1951), 34, 835-40) were then added, and the reaction mixture was stirred at 80° C. for another 1 h. After cooling to RT, the mixture was added to water. The suspension obtained in this manner was filtered off and the solid was washed repeatedly with water and then dried under high vacuum. This gave 196 mg (77% of theory) of the title compound in solid form.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O>C(Cl)Cl.CCN(CC)CC>[N:22]1([C:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[O:12])=[CH:19][CH:18]=2)=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: Nc1ccc(C(=O)N2CCCCC2)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2CCCCC2)cc1)c1n[nH]c2ccccc12
Reaction time: 16 h

Procedure:
To a solution of 100 mg 1H-indazole-3-carboxylic acid in 2 mL DCM and 0.3 mL NEt3, 125 mg (4-Amino-phenyl)-piperidin-1-yl-methanone and 157 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. After the addition of 5 mL water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent alkylation reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20]CC)=[O:19])=[CH:8][C:9]=1[NH:10]2.O.[OH-].[Li+]>C1COCC1.C(O)C.O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([OH:20])=[O:19])=[CH:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C(=O)O)ccc12
Temperature: 25 °C

Procedure:
A suspension of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (Intermediate 48-1, 1.81 g, 5.01 mmol) and lithium hydroxide monohydrate (0.601 g, 15.03 mmol) in THF-ethanol-water (3:1:1, 50 mL) was heated at reflux for 2 h. The mixture was cooled to rt and concentrated. The residue was stirred in water and treated with 1 M hydrochloric acid to pH 1-2. The precipitate was collected by filtration, washed with water, and dried to afford 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylic acid as a light brown solid (1.84 g, ca. 90% purity, 99%). 1H NMR (400 MHz, DMSO-d6) δ 12.95 (br. s., 1H) 12.02 (s, 1H) 8.69 (d, J=8.53 Hz, 1H) 8.47 (s, 1H) 8.28 (br. s., 1H) 7.94 (d, J=8.28 Hz, 2H) 7.87 (d, J=8.28 Hz, 1H) 7.65 (br. s., 1H) 7.51 (d, J=8.03 Hz, 1H). Mass spectrum m/z 331, 333 (M−H)−.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:30][C:31]1[C:35]([C:36]([OH:38])=O)=[CH:34][O:33][N:32]=1.[CH3:39][O:40][C:41]1[CH:61]=[CH:60][C:44]([O:45][C:46]2[CH:59]=[CH:58][C:49]([CH2:50][NH:51][C:52]([C:54]3([NH2:57])[CH2:56][CH2:55]3)=[O:53])=[CH:48][CH:47]=2)=[C:43]([C:62]([F:65])([F:64])[F:63])[CH:42]=1>CN(C=O)C>[CH3:39][O:40][C:41]1[CH:61]=[CH:60][C:44]([O:45][C:46]2[CH:59]=[CH:58][C:49]([CH2:50][NH:51][C:52]([C:54]3([NH:57][C:36]([C:35]4[C:31]([CH3:30])=[N:32][O:33][CH:34]=4)=[O:38])[CH2:55][CH2:56]3)=[O:53])=[CH:48][CH:47]=2)=[C:43]([C:62]([F:63])([F:64])[F:65])[CH:42]=1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Reactant: Cc1nocc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4conc4C)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
37 μL (0.26 mmol) of triethylamine and 84.4 mg (0.26 mmol) of TBTU were added to a solution of 33.4 mg (0.26 mmol) of 3-methylisoxazole-4-carboxylic acid in 5 mL DMF and the mixture was stirred for 10 min at RT. Then 100 mg (0.26 mmol) of 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide (from 85a) was added and the mixture was stirred for 4 h at ambient temperature and overnight at 40° C. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])=[CH:16][CH:15]=1
Reactant: Brc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(Br)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 78.2 %

Procedure:
In a 250 mL flask equipped with a nitrogen inlet, overhead stirring assembly, and reflux condenser were placed 4-nitrobenzoyl chloride (22.6 g, 0.122 mol), bromobenzene (100 g, 0.63 mol), and aluminum chloride (17.3 g, 0.13 mol). The mixture was heated for 3 h at 100° C., then cooled to room temperature and stirred for an additional 16 h. The mixture was poured into 1 L of acidic (HCl) ice water, and the organics were extracted using methylene chloride, dried over magnesium sulfate, and the solvents were removed under reduced pressure to yield a yellow powder. Recrystallization from acetone afforded 29.2 g (85% yield) of yellow crystals: m.p. 123°-124° C., (Lit. 122° C.). ##STR5##
Reaction SMILES: [CH3:1][C:2]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[C:5]([CH3:11])[O:4][N:3]=1.[NH2:12][C@H:13]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[CH3:1][C:2]1[C:6]([S:7]([NH:12][C@H:13]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)(=[O:9])=[O:8])=[C:5]([CH3:11])[O:4][N:3]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: Cc1noc(C)c1S(=O)(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 3,5-dimethyl-4-isoxazolesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 2H), 7.3-7.1 (m, 5H), 7.05 (t, 2H, J=6.5 Hz), 6.81 (d, 1H, J=7.1 Hz), 4.65 (dd, 1H, J=6.3, 2.2 Hz), 3.11 (t, 2H, J=7.2 Hz), 2.4 (m, 4H), 2.2 (s, 3H), 2.05 (m, 2H), 2.01 (s, 3H), 2.0-1.8 (m, 7H), 1.21 (d, 6H, J=7.1 Hz); ESMS m/e: 539.5 (M+H)+.